The Cree communities of James Bay might be at risk of contracting zoonoses from their contacts with wildlife. Evidence of exposure to seven zoonotic infections, namely Trichinella spp., Toxoplasma gondii, Toxocara canis, Echinococcus granulosus, Leptospira spp., Coxiella burnetii, and Francisella tularensis, was sought in sera from 267 residents of Chisasibi (166) and Waskaganish (101). Study participants responded to questionnaires documenting socio-demographic characteristics and hunting and trapping activities. Associations were assessed by univariable and multivariable logistic regression analysis. High seroprevalence rates were documented for Leptospira spp. (23%), Francisella tularensis (18%), and Toxoplasma gondii (9%). Seroprevalence rates of less than 5% were observed for Coxiella burnetii, Echinococcus granulosus, and Toxocara canis. No subject exhibited serological proof of Trichinella spp. exposure in either community. Serological evidence of exposure to Leptospira spp. and T. gondii was greater in Chisasibi than in Waskaganish, while the T. canis seroprevalence rate was higher in Waskaganish than in Chisasibi. Handling of rabbits was associated with seropositivity for Leptospira spp. Statistical trends were also detected between the handling of ducks and exposure to Toxoplasma gondii, and between both handling animals without gloves and springtime hunting activities and Leptospira spp. seropositivity in Chisasibi and Waskaganish, respectively. A review of the medical records revealed few clinical events potentially related to zoonotic exposures. However, public health authorities and health care workers in these communities should be alert to the risk of these zoonoses.