The effect of the nonsteroidal estrogenic compound, diethylstilbestrol (DES) on cell-mediated immunocompetence in the mouse has been assessed. Adult female B6C3F1 mice were injected (s.c.) with 0.2, 1.0 and 4.0 mg/kg of DES daily for 14 days. All immunological tests and toxicological parameters were determined at least 24 hr after the last exposure. Thymic involution and hepatomegaly were noted at the lowest dose of DES. The most sensitive indicator of immunosuppression by DES was the delayed hypersensitivity response (DHR) to keyhole limpet hemocyanin in mice sensitized without adjuvant. The lowest dose of DES produced a 93% decrease, compared with a 39% decrease for the same DHR model in mice sensitized to keyhole limpet hemocyanin plus adjuvant and a 63% decrease for the DHR to sheep erythrocytes. A 35% decrease of the acute inflammatory response to carrageenin was produced by the lowest dose of DES. Day 2 proliferative responses to both concanavalin A and phytohemagglutinin (T-cell mitogens) were depressed by the lowest dose of DES, whereas significant suppression of the response to lipopolysaccharide (B-cell mitogen) was only noted at the highest dose of DES. The effects of DES on Day 3 proliferative responses were less dramatic. The mixed lymphocyte response was significantly suppressed by 1.0 and 4.0 mg/kg of DES on all days in culture. The reversibility of the DES effects was studied by resting the mice for 30 days between exposure and measuring a given parameter. All effects on organ weights and the depression of both the sheep erythrocytes DHR and the carrageenin inflammatory response were reversed.