Previous genetic-response studies, usually without considering environmental factors, encountered great difficulties in replication of results. Although atypical antipsychotics are becoming the mainstay for schizophrenia treatment which makes an antipsychotic “atypical” remains unclear. Risperidone (a widely used atypical antipsychotic agent) and several other atypicals have high affinities for 5-HT6 and 5-HT7 receptors. This study investigated the effects of the T→C 267 polymorphism in the 5HT6 receptor gene and two rare Pro279Leu and Thr92Lys substitutions in the 5HT7 receptor gene on risperidone efficacy after rigorous control for nongenetic confounders. We found an association between the T→C 267 polymorphism of the 5HT6 receptor gene and response to risperidone in 123 acutely ill schizophrenia inpatients after adjustment for confounders. Compared to patients with the T/C 267 genotype, those with T/T 267 showed less severe positive symptoms (p=0.006) and general psychopathology (including anxiety, depression, and cognitive dysfunctions) (p=0.005). The T→C 267 polymorphism had no influences on negative symptoms. The two rare polymorphisms in the 5HT7 receptor gene were not observed in our sample. In conclusion, the 5HT6 receptor gene variant can affect risperidone response to positive symptoms and general psychopathology (but not negative symptoms) after control for nongenetic factors.