The failure of the Pazzi Conspiracy against Florence in 1480 and unexpected peace as a result of 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. Venice had ended its long conflict with the Ottoman Turks in 1479, with the Treaty of Constantinople, and was freed to turn its complete attention to its role in its terra firma (main land) and generally to the peninsula of Italy.
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 had taken possession of the strategic stronghold of Forlì in September 1480, with quick papal confirmation, and who now looked towards Ferrara in extending Della Rovere territory.
The immediate casus belli at the beginning of 1482, as usual was a minor infraction of prerogatives: Venice maintained a representative in Ferrara with the high title of visdominio, under whose care was the Venetian community in Este lands. In 1481, overreaching his mandate with 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. On this excuse, war was declared.
Allied with Venice, besides the papal troops and Riario, were contingents supplied by the Republic of Genoa and William VIII, Marquis of Montferrat. Taking Ferrara's side, loosely under the command of Federico da Montefeltro, duke of Urbino, were troops of Ercole's father-in-law Ferdinand of Naples, under his son Alfonso of Calabria, who invaded the Papal States from the south, as well as troops sent by Ludovico il Moro of Milan and by the lords of two cities threatened by the mainland power of Venice, Federico I Gonzaga of Mantua and Giovanni II Bentivoglio of Bologna.