OBJECTIVE: This study investigated the associations of plasma leptin levels with insulin resistance (IR) and prediabetes in relatively lean, rural Chinese men and women. DESIGN AND METHODS: This study included 574 subjects aged 21-45 years from a community-based twin cohort. Plasma leptin concentrations were measured by sandwich immunoassays using flowmetric xMAP technology. Prediabetes was defined based on fasting plasma glucose and 75-g oral glucose tolerance test. Multivariate linear and logistic regression analyses were used to investigate gender-specific associations of leptin with IR measures and prediabetes, adjusting for intra-twin correlation, measures of adiposity, and other pertinent covariates. RESULTS: The body mass index is 22.3+/-2.7 kg/m(2) in men and 22.5+/-2.7 kg/m(2) in women. Leptin levels were positively associated with IR. Individuals with higher tertiles of leptin also had increased risk of prediabetes with odds ratios (OR) of 2.6 (95% confidence interval (CI): 1.4-5.1) and 4.3 (95% CI: 2.1-8.7) in men; OR of 1.1 (95% CI: 0.6-2.1) and 3.1 (95% CI 1.5-6.2) in women for second and third tertile respectively. These associations were attenuated after further adjusting for adiposity measurements only in men. The leptin-prediabetes associations disappeared after adjusting for the homeostatic model assessment of IR in both genders. CONCLUSION: In this sample of relatively lean rural Chinese adults, plasma leptin levels were associated with IR and prediabetes in a dose-response fashion, which were not totally explained by adiposity. Our data emphasize that prediabetes is not all about obesity, and leptin may be an additional biomarker for screening individuals at high risk for prediabetes in this population.