The Italian War of 1494–1498 began when Ludovico Sforza, then Regent of Milan, invited Charles VIII of France to invade Italy, using the Angevin claim to the Kingdom of Naples as a pretext.

Both women wanted to ensure their children inherited the Duchy and when Isabella's father became Alfonso II of Naples in January 1494, she asked for his help in securing their rights.

He did so with support from his distant Trastamaran relative Ferdinand II of Aragon, who as ruler of the neighbouring Kingdom of Sicily viewed French expansion in Southern Italy as a threat.

[12] As a result, the Great Council was open to an alliance with France to remove Ludovico, although some members disagreed, including Agostino Barbarigo, the current Doge of Venice.

[12] In their initial talks, the Venetians demanded lands on both sides of the Adda river, which Louis considered excessive, while Venice rejected a French request for a subsidy of 100,000 ducats.

Under a deal brokered by Ercole I d'Este, Duke of Ferrara, Venice was granted Cremona along with lands on the eastern bank of the Adda, and agreed to pay part of Louis' expenses.

[13] The Treaty of Blois was signed on 9 February 1499, while Pope Alexander VI approved the invasion of Milan in exchange for the French backing Cesare Borgia's campaign in Romagna.

[18] As the summer campaign season of the year 1500 neared, Louis XII became worried about the intentions of newly unified Spain as he moved further into Italy, drawing his forces eastward.

[20] On 25 July 1501, Frederick IV of Naples abdicated in favour of Louis and died in French captivity in 1504; Francesco Guicciardini points out in the Discorso di Logrogno (1512) that the partition of the Mezzogiorno between the houses of Aragon and Orléans neglected to take into account the economic system of a region dominated by sheep-rearing and its concomitant transhumance.

During this campaign, a French knight, Charles de la Motte, was captured by Spanish forces and later used as a hostage after declaring his famous Challenge of Barletta on 13 February 1503.

[26] The French army under Italian ally, Francesco de Gonzaga was destroyed, with about 4,000 of just over 15,000 soldiers killed at Garigliano,[27] leaving Louis XII forced to abandon his current ambitions in Naples and, on 2 January 1504, the king withdrew to Lombardy.