Recent researches have implicated that mutations in the neurexin-3 (NRXN3) gene on chromosome 14q24.3-q31.1 might play a role in addiction, autism, and obesity. In order to explore the association of NRXN3 polymorphisms with schizophrenia, we examined seven single nucleotide polymorphisms (SNPs) in NRXN3 spanning 1.33. Mb of this gene, in a Chinese Han sample of 1214 schizophrenic patients and 1517 healthy control subjects. Our results showed that three SNPs were associated with schizophrenia (rs7157669: A. >. C, p= 0.006; rs724373: C. >. T, p= 0.014; rs7154021: C. >. T, p= 0.018). After being corrected for multiple tests, the association of rs7157669 remained significant but those for two others were modest. According to the linkage disequilibrium pattern, the 7 SNPs may construct 3 haplotype blocks. Several haplotypes were significantly associated with schizophrenia, constructed by rs11624704-rs7157669-rs724373 (AAC, p= 0.003; ACT, p= 0.007, both remained significant after permutation tests), rs7154021-rs7142344 (TT, p= 0.024; CT, p= 0.012), respectively. Among the patients, 326 ones at first onset have received 6-week monotherapy of risperidone. Further analyses showed that two SNPs were associated with percentage of bodyweight gain following a 6-week therapy of risperidone (rs11624704: p= 0.03; rs7154021: p= 0.008) and rs7154021 remained significant after permutation test. Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia and have a role in bodyweight gain related to therapy of risperidone in Chinese Han population. © 2012 Elsevier Inc.