Adiponectin is secreted exclusively by adipocytes. Adiponectin is regulated by obesity, smoking, and genetic factors, including CDH13, which may contribute to development of diseases such as cardiovascular disease. Therefore, we aim to explore the joint effect of smoking and obesity on the association between CDH13 (rs3865188) and adiponectin among Korean men. This study included 1,570 Korean men aged 40-69 years who participated in the KARE cohort study (community-based cohorts, South Korea) from 2001. Hypoadiponectinemia was defined as the lowest quartile of adiponectin. In this study, individuals with at least one at-risk allele, the T allele, had an increased risk for hypoadiponectinemia, particularly current smokers with at least one T allele together with obesity when compared to those without the T allele. In addition, individuals with the TT genotype of CDH13 rs3865188, as well as obesity, were significantly associated with a 1.8-fold (odds ratio (OR) = 9.4, 95% confidence interval (CI) = 4.4-19.6, P < 0.001) increased risk for hypoadiponectinemia compared to individuals with the TT genotype of CDH 13 rs3865188 and normal waist circumference (WC) (OR = 5.1, 95% CI = 3.5-7.6, P < 0.001). However, in the joint effect of smoking and obesity, current smokers with the TT genotype of CDH13 rs3865188, as well as obesity, were significantly associated with a 6.2-fold (OR = 24.2, 95% CI = 3.0-196.6, P < 0.001) increased risk for hypoadiponectinemia compared to nonsmokers with the TT genotype of CDH 13 rs3865188 with normal WC (OR = 3.9, 95% CI = 1.7-9.3, P < 0.001). This study suggested that the association between CDH13 and adiponectin can be modified by lifestyle factors, such as smoking and obesity, among Korean men.