Although there has been renewed interest in the serotonin (5-HT) system in schizophrenia, direct evidence for 5-HT dysfunction is limited. This study compares the responses of m-chlorophenyl-piperazine (mCPP), a 5-HT agonist, in first-episode schizophrenia and a known psychotogenic dopamine agonist, methylphenidate. Eighteen patients experiencing their first episode of psychosis and eight healthy controls received methylphenidate (0.5 mg/kg) and mCPP (0.1 mg/kg) intravenously. Behavioral assessments were done before and after the procedure, and a peak response to each agent was rated. Methylphenidate, but not mCPP, produced psychotic symptoms in patients. mCPP did decrease anxiety, hallucinations, and anger and increased agitation, somatic concern, and impaired understandability. Both agents had limited effects on controls. In conclusion, unlike methylphenidate, mCPP did not produce psychotic symptom activation in schizophrenic patients in, and its effects appeared to be nonspecific.