Background Metabolic syndrome (MetS) associated with psychiatric disorders and psychotropic treatments represents a major health issue. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is an enzyme that catalyzes tissue regeneration of active cortisol from cortisone. Elevated enzymatic activity of 11 beta-HSD1 may lead to the development of MetS. Methods We investigated the association between seven HSD11B1 gene (encoding 11 beta-HSD1) polymorphisms and BMI and MetS components in a psychiatric sample treated with potential weight gain-inducing psychotropic drugs (n = 478). The polymorphisms that survived Bonferroni correction were analyzed in two independent psychiatric samples (n(R1) = 168, n(R2) = 188) and in several large population-based samples (n(1) = 5338; n(2) = 123 865; n(3) > 100 000). Results HSD11B1 rs846910-A, rs375319-A, and rs4844488-G allele carriers were found to be associated with lower BMI, waist circumference, and diastolic blood pressure compared with the reference genotype (P-corrected < 0.05). These associations were exclusively detected in women (n = 257) with more than 3.1 kg/m(2), 7.5 cm, and 4.2 mmHg lower BMI, waist circumference, and diastolic blood pressure, respectively, in rs846910-A, rs375319-A, and rs4844488-G allele carriers compared with noncarriers (P-corrected < 0.05). Conversely, carriers of the rs846906-T allele had significantly higher waist circumference and triglycerides and lower high-density lipoprotein-cholesterol exclusively in men (P-corrected = 0.028). The rs846906-T allele was also associated with a higher risk of MetS at 3 months of follow-up (odds ratio: 3.31, 95% confidence interval: 1.53-7.17, P-corrected = 0.014). No association was observed between HSD11B1 polymorphisms and BMI and MetS components in the population-based samples. Conclusions Our results indicate that HSD11B1 polymorphisms may contribute toward the development of MetS in psychiatric patients treated with potential weight gain-inducing psychotropic drugs, but do not play a significant role in the general population. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.