Abstract Context Systemic inflammation plays a pivotal role in the development of type 2 diabetes (T2D). Objective We hypothesized that circulating levels of calprotectin, a myeloid cell-derived biomarker of inflammation, is associated with the development of new-onset T2D in the general population. Methods A total of 4815 initially nondiabetic participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND), a prospective population-based cohort study, were assessed for plasma levels of calprotectin at baseline. Circulating levels of calprotectin were investigated for potential associations with the risk of new-onset T2D, defined as a fasting plasma glucose level of 7.0 mmol/L or greater, a random plasma glucose level of 11.1 mmol/L or greater, a self-reported physician-based diagnosis of T2D, the use of glucose-lowering drugs, or any combinations thereof. Results Median plasma calprotectin levels were 0.49 (0.35-0.69) mg/L. Plasma calprotectin levels were significantly associated with the risk of new-onset T2D (hazard ratio [HR] per doubling 1.42 [95% CI, 1.22-1.66]; P < .001). The association remained independent of adjustment for age and sex (HR 1.34 [95% CI, 1.14-1.57]; P < .001), but not after further adjustment for potentially confounding factors (HR 1.11 [95% CI, 0.90-1.37]; P = .326), with adjustment for hyperlipidemia and high-sensitivity C-reactive protein explaining the loss of significance. Stratified analyses showed significant effect modification by hypertension, history of cardiovascular disease (CVD), the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (Pinteraction ≤ .001 for each), and the use of lipid-lowering drugs (Pinteraction ≤ .05), with higher HRs in individuals without hypertension, without history of CVD, with below-median HOMA-IR, and in those not using lipid-lowering drugs. Conclusion Elevated plasma levels of calprotectin are associated with a higher risk of developing T2D in the general population and may represent a moveable inflammatory biomarker. This association, however, does not represent a direct effect, and seems dependent on hyperlipidemia and systemic inflammation.