Abstract The goal of this study was to examine the disruptive effects of municipal effluents on the immune and reproductive systems of freshwater mussels. For 30 days, caged mussels were immersed in the Rivière des Mille Îles (Quebec, Canada), 150 m both upstream and downstream from two urban wastewater treatment plants: station F (Fabreville) and station A (Auteuil), which serve the city of Laval. Station F is 12 km upstream from station A. The immune and reproductive statuses of the mussels were thereafter determined. Though the weight/shell length ratio was not affected, the effluent induced mortality up to 60% at downstream sites. Total hemocyte counts increased, and phagocytosis and lysozyme activities were induced at station F, whereas these responses were suppressed at station A. Heterotrophic bacteria levels in mussels were negatively correlated with phagocytosis, showing the importance of this process in defending against infection. Inflammation biomarkers such as nitric oxide and cyclooxygenase activity were the same for all sites but were positively correlated with phagocytosis activity. The production of vitellogenin (Vtg)-like proteins was significantly induced at the site downstream from station A and was strongly associated with phagocytosis. This was further supported through analysis of covariance, of Vtg responses against phagocytosis, revealing that Vtg was no longer induced at the sites upstream and downstream from station A. The data support the contention that Vtg was involved, in part at least, in the immune system in mussels. Both Vtg and immune status are impacted by urban effluents and should be considered when using the Vtg biomarker to search for the presence of (xeno)estrogens in contaminated environments.