We examined the association of the RETN (resistin) -420 C>G polymorphism (rs1862513) with risk of diabetes mellitus (DM), considering lifestyle factors, in Japanese. Subjects were participants of J-MICC Study, where 2,651 participants aged 35-69 years provided their blood for genotyping and lifestyle data after informed consent. Odds ratio (OR) of DM for RETN-420 G/G genotype was estimated using unconditional logistic regression model. Statistically significant interaction on risk of DM was observed between RETN-420 G/G genotype and BMI<25 (OR for interaction = 0.12; P = 0.046), and when subjects with RETN-420 C/C+C/G and BMI ≥ 25 (n = 69 for DM and 544 for non-DM) were defined as the reference, the adjusted ORs for subjects with RETN-420 G/G genotype and BMI>25 (n = 10 for DM and 111 for non-DM), RETN-420 C/C+C/G and BMI<25 (n = 81 for DM and 1,605 for non-DM), and RETN-420 G/G and BMI<25 (n = 1 for DM and 230 for non-DM) were demonstrated to be 0.72 (95% confidence interval: 0.36-1.46), 0.40 (0.28-0.56) and 0.03 (0.005-0.25), respectively. The present study revealed the significant interaction of RETN-420 G/G genotype with lower BMI on the decreased risk of DM, but the direction was opposite to the reported ones in Japanese. We should be careful in interpretation of the present study results because of the limited sample sizes. Further investigation of this association as well as of the actual biological roles of RETN in the genesis of human metabolic disorders including DM will be required.