Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT1A receptor-effector system complex possibly involving subsensitivity of the 5-HT1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.