The application of pharmacogenetics is currently one of the most promising developments in anti-psychotic treatment and is attracting more and more attention. Although risperidone belongs to the first-line atypical anti-psychotics, there have been relatively few risperidone pharmacogenetic studies, especially in Asian populations. We investigated the relationship between the C825T polymorphism of GBN3 (rs5443) and the -1019 C/G polymorphism of 5-HT(1)A (rs6295) and response to risperidone treatment. One-hundred and thirty schizophrenia patients were recruited. They were treated with risperidone monotherapy for eight weeks. Clinical response was assessed on the Positive and Negative Syndrome Scale (PANSS) on the day of admission and was subsequently assessed after eight weeks following the treatment. Patients were genotyped for two functional polymorphisms: C825T of GBN3 (rs5443) and -1019 C/G of HT(1)A (rs6295). Association tests between genotypes and percentage improvement in total PANSS scores, as well as positive symptom scores and negative symptom scores, were performed using analyses of variance (ANOVA). The -1019 C/G polymorphism of HT(1)A (rs6295) was associated with negative symptom response to treatment. Patients with the CC genotype showed substantial improvement as regards negative symptom response (F = 4.177, df = 2, P = 0.019), compared with the patients with the CG and GG genotypes. No association was observed between C825T of GBN3 (rs5443) and changes in PANSS scores. The results suggest that the -1019 C/G polymorphism (rs6295) in the 5-HT(1)A gene may be a useful predictor of reduction in negative symptoms in schizophrenic patients treated with risperidone.