In 1644, Guercino was commissioned the altarpiece depicting Saint Helena adoring the Cross for the church of San Lazzaro dei Mendicanti in Venice, still in situ and the only public work by the master from Cento in a city whose artistic scene in the seventeenth century was characterised by a significant presence of foreign artists and a climate of lively competition. In the light of the most recent studies dedicated to Guercino, the research conducted on patronage and collecting in the seventeenth century in the lagoon over the last two decades and new documentary evidence, this contribution examines the painter’s relations with his Venetian clientele, in which personal relations with patrons, professional relations with intermediaries and agents, and competition with local painters are intertwined in a market populated by collectors who had expressed a particular appreciation for the Bolognese school of painting.