With Cesare away in France brokering the new French King's divorce and Lucrezia joining her husband in Naples, Rodrigo is in Rome trying to deal with a very singular problem, once again orchestrated by Caterina Sforza: Bianca Gonzaga, the Mantuan Duke Francesco's wife, is overstaying her welcome in the Pope's bedroom and behaving erratically. Seemingly unstable and constantly quoting the Bible, Bianca's roaming the Vatican like a ghost and soon ends up in little Giovanni's room, where the Pope's grandson, left to his and Vanozza's care, is sleeping soundly. Just before Bianca has a chance to do anything with the child, his nursemaid enters and forces Bianca to first hide herself and then leave, thinking she has found the key to the Pope's heart.
The next day, just as Rodrigo is repeating his request to have her leave the Vatican in order to avoid scandal, she pridefully announces that she bears the Pope's child, one that will support him now that his other children are away and one that will cast his sorrow away. The confused Rodrigo asks a medic to examine her and the findings are shocking: Bianca's not with child but she recently was, her having it brutally torn from her womb being the reason that she was driven insane.
Left with no other option, a heart-broken Rodrigo tries to have Bianca removed to a convent but as she is led out of his rooms, she escapes the nuns and armed with a dinner knife barricades herself inside little Giovanni's bedroom. Rodrigo, full of fear and panic, breaks down the doors to Giovanni's chambers, only to find that Bianca has killed herself due to the baby's absence. Ascanio Sforza comes to the sad Pope's rescue and vows to repay Gonzaga's inhuman scheme: behind the pretext of officially demanding his wife's statement for the papal annulment, Sforza visits Francesco Gonzaga and plants Bianca's dead body in the Duke's appartments, blaming him for her untimely demise.
Cesare, now the Duke of Valentinois, arrives in Avignon and is greeted by the imperious Archbishop d'Amboise, who informs him that French King is indisposed and can't officially greet him, as the Pope's emissary deserves. Later, Cesare meets with the Florentine operative Machiavelli, who's leaving the French court with his business concluded, and gives him some tips to help him earn the French King's favour: Cesare is to appear serious and modest, since the French, that are martial in nature, despise display of wealth and arrogance.
Cesare is then informed by Archbishop d'Amboise that France's barren Queen Consort still resides in the palace and thus, Cesare is not yet to hint at the annulment and must first earn the respect and trust of King Louis XII. Cesare is as always smooth and capable, handling both Louis XII and his wife well, even though the latter is haughty and offensive, but not uncomely at all. In search of a wife, Cesare considers the option of marrying Charlotte d'Albret, a refreshingly practical and beautiful noblewoman that seems to have no problem with their eventual separation and is only interested in bearing him strong heirs to perpetuate their line.
Soon, Cesare strikes a deal with the French King, with some help of the facilitator Archbishop d'Amboise, who is himself promised a cardinalate: not only will Cesare marry Charlotte and gain a prosperous dowry, he will also receive honours from King Louis XII, as well as the command of his considerable army, that will once again invade Italy, this time with the target being not Naples, but the Sforzas' Milan. Cesare grants the papal brief of annulment in return and after the Queen is summarily banished from the French King's bed and his court, Cesare is wed to Charlotte, who has no problem with being a simple distraction or political match rather than the real, sole object of his affection, that belongs to Lucrezia, and the couple stays on good terms, even as Cesare's departs France the next day, escorted by Archbishop d'Amboise who is the new French ambassador to the papal court.
Lucrezia, escorted by Cesare's trusted arch-henchman Micheletto, arrives at Naples, only to realize that King Ferdinand is as adamant as ever that her illegitimate son Giovanni should not be allowed to attend his court and her husband Alfonso of Bisceglie just as spineless and silently powerless on the subject as he previously was.
Driven by fury and an accidental meeting with a shady forest herbalist while hunting, Lucrezia starts plotting against Ferdinand with a recipe of poisonous mushrooms. Micheletto, worried for his lady's state of mind and her safety, warns her off the scheme that is likely to backfire and advises her to wait for the right time and the right weapon to complete her plan.
Unable to tolerate having Lucrezia's hands stained with blood, thinking that it wouldn't be Cesare's wish, Micheletto steps in to kill Ferdinand himself: separating him from his entourage during another hunting trip in the woods, Micheletto and Ferdinand approach a puddle filled with flesh-eating eels, designed from Ferdinand's father, mad old King Ferrante as a device to torture and eliminate his enemies. Ferdinand is soon pushed into the puddle by Micheletto, who stands by as the King's entourage ultimately finds him savagely devoured by the eels. Spreading mourning to all his relatives but Lucrezia, Ferdinand is carried back to his palace dead, and Micheletto informs Lucrezia that now the choice to bring her son to the duplicitous and dilapidated Naples is hers alone.
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