Metabolic disturbances are more prevalent in patients with schizophrenia (SCZ) than in the general population. The endocannabinoid system plays an important role in the regulation of dopamine transmission and several metabolic pathways, and the endocannabinoid receptor type 1 gene (CNR1) is considered a candidate gene for both SCZ and metabolic disorders. We examined whether genetic variation in CNR1 was associated with metabolic syndrome (MetS) in a naturalistic cohort of 407 patients with SCZ. The minor alleles of rs6928499, rs1535255, and rs2023239 were nominally associated with a lower risk of MetS [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.37-0.84; P = 0.006; OR, 0.56; 95% CI, 0.37-0.84; P = 0.006; and OR, 0.44; 95% CI, 0.27-0.72; P = 0.001, respectively, adjusted for age, sex, duration of illness, clozapine or olanzapine treatment). These differences were mainly due to differences in high-density lipoprotein cholesterol and fasting glucose but not in body mass index or waist circumference. No significant association of the other polymorphisms (rs806377, rs1049353, rs6454674, and rs806379) with MetS was found. These results provide evidence that the prevalence of MetS is associated with the CNR1 gene in patients with SCZ during long-term treatment with antipsychotic treatment. Further studies are needed to uncover the exact molecular basis for this association, which could provide novel treatment targets for the MetS.