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Context: Impairment of immune and inflammatory homeostasis is reported to be one of the causal factors of diabetes. However, the association of complement C3 levels with incident diabetes in humans remains unclear., Objective: This study aimed to examine the association between C3 levels and incident type 2 diabetes mellitus (T2DM), and further explore the potential mediating role of body mass index (BMI) in C3-T2DM associations., Methods: We determined serum C3 levels of 2662 nondiabetic middle-aged and elderly (64.62 ± 7.25 years) individuals from the Dongfeng-Tongji cohort at baseline. Cox regression was employed to examine the incidence of T2DM in relationship to C3 levels during 10 years of follow-up. Mediation analysis was further applied to assess potential effect of BMI on the C3-T2DM associations., Results: Overall, 711 (26.7%) participants developed T2DM during 23 067 person-years of follow-up. Higher serum C3 was significantly associated with higher risk of incident T2DM after full adjustment (HR [95% CI] = 1.16 [1.05, 1.27]; per SD higher). Compared with the first quartile of C3 levels, the HR in the fourth quartile was 1.52 (95% CI = [1.14, 2.02]; Ptrend = 0.029). Robust significant linear dose-response relationship was observed between C3 levels and BMI (Poverall < 0.001, Pnonlinear = 0.96). Mediation analyses indicated that BMI might mediate 41.0% of the associations between C3 and T2DM., Conclusion: The present prospective study revealed that C3 could be an early biomarker for incident T2DM, and that BMI might play a potential mediating role in the C3-T2DM associations, which provided clues for the pathogenesis of diabetes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)