In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.