The immune system is considered to be an energetically expensive component of an individual's life history. Investment in the immune system can depend on the environment that an individual finds itself in. The American mink, Neovison vison, exists in the natural environment and on fur farms. The natural environment and mink farm differ in many ways, such as wild mink being exposed to many parasites that are less prevalent and less abundant in the domestic environment because of veterinary care. We collected free-ranging mink from commercial trappers and domestic mink from fur farmers in Ontario and Nova Scotia, Canada, and examined relative spleen mass. Wild male mink had larger spleens than domestic mink in Nova Scotia, with a similar trend in Ontario. Female mink that escaped from farms (feral) in Nova Scotia had significantly larger spleens than their domestic counterparts on the farms. Both of these results are consistent with the prediction that the natural environment contains parasites and pathogens that require enhanced investment in the immune system. In Nova Scotia, females had larger spleens than males, whether considering wild or domestic populations. Finally, wild mink showed greater condition dependence of spleen mass than domestic populations. Further investigations should include experimental approaches such as providing veterinary care to wild populations to assess the effects of parasites and pathogens on the immune system. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, 107, 624–631.