Stress usually has a depressing effect on immune function. However, we observed apparent immune enhancement following restraint stress. Fischer 344 rats were restrained in snug--fitting wire mesh tubes for 14 hr/day during the light portion of a daily 14:10 hr light/dark cycle for 0, 11, 22, or 33 days. Animals were sacrificed immediately after the last restraint session, and trunk blood and spleens were collected. Blood neutrophil percent was significantly higher after 11 or 22 days of restraint than in controls, as expected, and returned to baseline at 33 days. However, natural killer activity of spleen cells against Yac-1 targets, measured by a lactate dehydrogenase (LDH) release assay, was higher than controls after all periods of restraint, and especially after 11 days. Responses to concanavalin A by spleen cells from restrained rats were also higher than controls after all periods of restraint.