The effect that cotreatment with 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) was determined in female B6C3F1 mice. Groups of eight mice per group were given a single oral dose of PCB153 alone (0, 3.58, 35.8, or 358 mg/kg), TCDD alone (0, 0.1, 1, or 10 micrograms/kg), and all possible combinations of these doses in corn oil 7 days prior to immunization with SRBCs. Separate groups of mice were given phenobarbital (PB) parenterally by intraperitoneal injection at a dosage of 160 mg/kg/day for 3 days. Four days after intravenous immunization, body, spleen, thymus, and liver weights and the PFC response to SRBCs were determined. Exposure to TCDD alone resulted in a dose-related suppression of the PFC response, with significant suppression at 1 and 10 micrograms/kg. In contrast, exposure to PCB153 alone resulted in the enhancement of the PFC response at 358 mg/kg. Combined exposure to 358 mg/ kg PCB153 and TCDD resulted in no change (PCB153 + 0.1 microgram/ kg TCDD) or suppression (PCB153 + 1 or 10 micrograms/kg TCDD) of the PFC response relative to PCB153 alone; however, the PFC response was enhanced (PCB153 + 0.1 microgram/kg TCDD), unaffected (PCB153 + 1 microgram/kg TCDD), or suppressed (PCB153 + 10 micrograms/kg TCDD) relative to corn oil controls. PB did not affect the PFC response to SRBCs, despite a 13-fold induction of hepatic pentoxyresorufin O-dealkylase (PROD) activity. These results suggest that PCB153 enhancement of the PFC response is not related to PROD induction and that it acts as a functional antagonist rather than an aryl hydrocarbon receptor or dispositional antagonist. By enhancing the PFC response to SRBCs, PCB153 raises the "setpoint" response level. Consequently, cotreatment with an immunosuppressive dose of TCDD fails to suppress the PFC response relative to corn oil controls, while clearly suppressing it relative to the appropriate control, PCB153 alone.