Wild animals, unlike their laboratory counterparts, live amidst an abundance of pathogens and parasites. The presence of such immune stimulation from the time of birth likely has a profound effect on the development and stasis of the immune system. To probe potential differences between the immune systems of wild and laboratory animals, the response to mitogen (Con A) of splenocytes from wild rats was evaluated in vitro and compared with results from lab-rat-derived splenocytes. Although the response to mitogen is ubiquitous in splenocytes from laboratory animals regardless of strain or even species, splenocytes derived from wild rats were unresponsive to mitogen as judged by upregulation of activation markers and proliferation. Further, splenocytes from wild rats produced almost 10-fold less IL-2 and TNF-α in response to mitogen than did splenocytes from laboratory rats. In addition, mitogen stimulation resulted in an almost 100-fold greater production of IL-4 in wild-rat-derived splenocytes than in lab-rat-derived splenocytes. Perhaps surprisingly, these differences were observed in the absence of differences between wild and laboratory animals in the ratio of CD4+/CD8+ T cells or in the relative numbers of T cells, B cells and monocytes in the splenocyte population. These observations may have substantial implications for the hygiene hypothesis and provide considerable insight into the roles played by the environment during immune system development and modulation.