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Objective: The serotonin 5-HT 1A receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT 1A receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment. Method: Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the –1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months. Results: The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms. Conclusions: These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.