Freshwater molluscs play an important role in aquatic ecosystems, providing food for many fish species and vertebrates. Investigations on factors that determine mollusc species richness and distribution in wetland systems are scarce in the Neotropical region. The main goal of this study was to determine how much variation in mollusc richness and composition is explained by area, hydroperiod, altitude, water conductivity, and dominant aquatic vegetation. This survey was performed in an extensive area of a Neotropical region (approximately 280,000 km(2) in southern Brazil), with a large number of wetland systems (111) and covering a wide gradient of altitude and wetland surface area. The mollusc richness was positively associated with wetland area and negatively associated with altitude. The richness and composition of the freshwater molluscs were similar between permanent and intermittent wetlands and it did not differ significantly between aquatic bed and emergent wetlands. The first three axes of CCA explained 16.2% of the total variation in the composition of the freshwater mollusc observed. The variation in the composition had a correlation with wetland area, altitude and water conductivity. Our results showed that the wetlands are important habitats for molluscs in southern Brazil, and that the richness and the composition of molluscs were associated with area, altitude, water conductivity and dominant vegetation.