Rat splenocytes were provoked to lipid peroxidation in a dose-dependent manner by cumene hydroperoxide. After exposure to cumene hydroperoxide, formation of high molecular weight protein, presumably through cross-linking of lower molecular weight protein, was stimulated in splenocytes as well as in erythrocyte ghosts. The mitogenic response to concanavalin A of splenocytes was remarkably depressed by addition of cumene hydroperoxide to cultures. This depression was due rather to failures of splenocytes in responding to concanavalin A than deactivation of concanavalin A molecules. It is notworthy that the viability of splenocytes was unaffected by cumene hydroperoxide under the culture conditions where the mitogenic response was depressed. The addition of alpha-tocopherol or thiourea could block the depression of mitogenic response by cumene hydroperoxide, indicating that the depressed response to concanavalin A was related to radical formation. Overall evidence suggests that the function of immunocompetent cells can be depressed through lipid peroxidation-associated mechanisms without suffering from lethal damage.