Glucocorticoids, secreted in response to perceived stress, can suppress immunoglobulin (Ig) levels and compromise immune function in mice and rats. Prairie voles (Microtus ochrogaster) have been reported to exhibit basal corticosterone concentrations that would cause pathological changes in the immune function of most other rodents. The goals of the present study were to verify that serum corticosterone concentrations are high in prairie voles, as compared with house mice (Mus musculus), by measuring serum corticosterone with the same RIA; to examine the effects of mild stressors on corticosterone response in both species and to examine the effects of elevated corticosterone levels on IgM and IgG levels in prairie voles and house mice. After 2 weeks of randomly timed 15-min daily restraint or cold-water swim sessions, animals were injected with sheep red blood cells. The data confirmed that basal blood concentrations of corticosterone were higher in prairie voles than house mice, but these high levels doubled after the first swim session in prairie voles, indicating that the adrenals can respond to stressors by producing increased corticosterone. After stress, antibody production (both IgM and IgG) was reduced in house mice but not in prairie voles, despite higher blood concentrations of glucocorticoids in prairie voles. Although body mass was statistically equivalent between species, prairie voles and mice differed dramatically in adrenal and splenic masses. Average adrenal mass of prairie voles was approximately three times the average mass of these organs in house mice; in contrast, the average splenic mass of house mice was approximately three times that of prairie voles. These data may be relevant to seasonal changes in immune function and survival.