Background: Manganese is both an essential element and a known toxicant, and it plays important roles in many mechanisms in relation to type2 diabetes (T2D). However, epidemiological studies of this relationship are rare. Objective: We investigated the association between plasma manganese and newly diagnosed T2D as well as whether the association could be modified by manganese superoxide dismutase (MnSOD) polymorphisms. Methods: We conducted a case-control study of 3,228 participants in China: 1,614 T2D patients and 1,614 controls. Concentrations of plasma magnesium were measured, and all participants were genotyped for the MnSOD Val16Ala polymorphism (rs4880). Results: A U-shaped association was observed between plasma manganese and T2D, with increased odds ratios (ORs) in relation to either low or high plasma manganese levels. Compared with the middle tertile, the multivariate-adjusted ORs [95% confidence intervals (CIs)] of T2D associated with the lowest tertile and the highest tertile of plasma manganese were 1.89 (1.53, 2.33) and 1.56 (1.23, 1.97), respectively. In spline analysis, the U-shaped association was consistently indicated, with the lowest odds of T2D at the plasma manganese concentration of 4.95 mu g/L. Minor allele frequencies (C allele) of the MnSOD Val16Ala polymorphism (rs4880) in the normal glucose tolerance (NGT) and the T2D groups were 13.57% and 14.50%, respectively. The MnSOD rs4880 polymorphism was not associated with T2D, and no interaction was found between plasma manganese and the MnSOD rs4880 polymorphism in relation to T2D. Conclusions: Our results suggested a U-shaped association between plasma manganese and T2D; both low and high levels of plasma manganese were associated with higher odds of newly diagnosed T2D. The U-shaped association was not modified by the MnSOD rs4880 polymorphism.