Irisin, a novel exercise-induced myokine, has been suggested to regulate energy homeostasis and insulin sensitivity. However, it remains unclear whether circulating irisin plays a role in the development of DM in human. We investigated the possible association between circulating irisin levels and incident DM in a 2.6-year longitudinal study of a population-based cohort comprised of rural Korean subjects. We conducted a longitudinal study within the Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population (KoGES-ARIRANG) study from November 2005 to January 2008. Cases (n=85) were patients with incident DM during the follow-up period and controls (n=85) were matched to incident DM cases based on sex and age at baseline. The relative risk of serum irisin/adiponectin level for incident DM was analyzed using conditional logistic regression analysis. Baseline irisin-ENREF-1 levels were significantly higher in subjects who developed DM than in subjects who did not. The serum irisin level was positively associated with glycated hemoglobin (HbA1c) and postprandial glucose. Irisin was negatively associated with adiponectin (R=-0.189, P=0.014). After adjustment for potential confounders, including body mass index, the odds ratios [95% confidence intervals] for incident DM increased in a graded manner as the serum irisin level increased (Quartile 1 vs Quartile 2 vs Quartile 3 vs Quartile 4=1 vs 0.80 [0.28-2.35] vs 3.33 [1.11-10.00] vs 4.10 [1.35-12.44], respectively), whereas the odds ratios for incident DM decreased in a graded manner as the serum adiponectin level increased. High serum irisin was independently associated with the development of DM, indicating that irisin may be a useful predictor of DM in Korean adults.