OBJECTIVE: Reduced circulating omentin levels have been reported in obesity and type 2 diabetes, but data were mostly derived from univariate analyses in small study samples. This study aimed to investigate the relationship between omentin, abnormal glucose tolerance and related metabolic factors in a large population-based cross-sectional study. DESIGN AND METHODS: Serum omentin was measured by ELISA in 1092 participants of the German KORA F4 survey (2006-2008). Associations between omentin serum levels, glucose tolerance (assessed with an oral glucose tolerance test) and diabetes-related factors were estimated using logistic and linear regression models respectively. RESULTS: Serum levels of omentin were not related to categories of glucose tolerance. However, serum omentin was positively associated with whole-body insulin sensitivity index (ISI (composite)) and HDL cholesterol and showed inverse associations with 2-h post-load glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance, BMI and triglycerides (all P≤0.03 after adjustment for age, sex and lifestyle factors). Further adjustment for BMI and/or serum lipids attenuated the associations with parameters of glucose metabolism, whereas adjustment for serum adiponectin virtually abolished all aforementioned associations. In contrast, adjustment for omentin had no effect on the positive association between adiponectin levels and ISI (composite). CONCLUSIONS: The data from this large population-based cohort show that circulating omentin levels are associated with insulin sensitivity. Our observations further suggest that omentin acts via upregulation of adiponectin, which in turn affects lipid metabolism and thereby also indirectly enhances insulin sensitivity, but mechanistic studies are required to corroborate this hypothesis.