Intravenous self-administration of cocaine is extremely sensitive to the effects of antipsychotic drugs, making this behavior a useful screen for neuroleptic potency. A possible interaction between female sex hormones and antipsychotic activity was investigated, using increased rates of cocaine self-administration as a measure of neuroleptic action. We found that female rats were more sensitive to haloperidol than were male rats. Female rats treated with a single injection of the antiestrogen tamoxifen 24 hr prior to test showed a significantly reduced response to haloperidol. The normal response was found to have recovered by one week following the tamoxifen treatment. Tamoxifen had no significant effect in male rats. These data, along with previous observations, indicate that ovarian function can greatly influence the behavioral response to antipsychotic drugs. To the extent that the self-administration model may reflect the potency of an antipsychotic drug, these data may indicate that female rats are more sensitive to the activity of neuroleptic drugs. Secondly, pretreatment with tamoxifen results in a significant attenuation of the activity of haloperidol.