The failure of the Pazzi Conspiracy against Florence in 1480 and the unexpected peace resulting from Lorenzo de' Medici's daring personal diplomacy with Ferdinand I of Naples, the Pope's erstwhile champion, was a source of discontent among the Venetians and Pope Sixtus IV alike. With the Treaty of Constantinople of 1479, Venice had ended its long conflict with the Ottoman Turks, and was freed to turn its whole attention to its role in its terra firma (main land) and to the peninsula of Italy more generally.
In addition to the usual minor friction over strongholds along the borders, there was a contest over the commerce in salt, which was reserved to Venice by a commercial pact. Nevertheless, Ferrara, which was ruled by Ercole I d'Este, had begun to take control over the saltworks at Comacchio. This appeared to be a threat to mainland interests of the Serenissima.
Venice was supported by Girolamo Riario, lord of Imola and Forlì – the nephew of Pope Sixtus – who, having taken possession of the strategic stronghold of Forlì in September 1480, and having received swift papal confirmation, now looked towards Ferrara to extend Della Rovere territory.
The immediate casus belli at the beginning of 1482 was, as usual, a minor infraction of prerogatives: Venice maintained a representative in Ferrara with the high title of visdominio, under whose care lay the Venetian community in Este lands. In 1481, overreaching his mandate by the arrest of a priest for debt, the visdominio was excommunicated by the vicar of the bishop of Ferrara, and forced out of the city. This was made the excuse for the declaration of war.
In alliance with Venice, besides the papal troops and those of Riario, were contingents supplied by the Republic of Genoa and William VIII, Marquis of Montferrat. Taking Ferrara's side, which was loosely under the command of Federico da Montefeltro, duke of Urbino, were troops of Ercole's father-in-law Ferdinand of Naples, led by his son Alfonso of Calabria, who invaded the Papal States from the south. Ferrara was also supported by troops sent by Ludovico il Moro of Milan, and those of Federico I Gonzaga of Mantua and Giovanni II Bentivoglio of Bologna, lords of two cities threatened by the mainland power of Venice, .