Neurobiological research suggests a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Genetics offer an opportunity to disentangle its involvement in the disease vulnerability vs an influence on antipsychotics' effects. The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) in schizophrenia and/or therapeutic response to atypical antipsychotics was assessed in a cohort of 133 French schizophrenic patients compared to 141 normal control subjects. No difference in 1359G/A polymorphism was observed between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. The G allele of the CNR1 gene polymorphisms could be a psychopharmacogenetic rather than a vulnerability factor regarding schizophrenia and its treatment.