The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.