OBJECTIVE - We reported strong relations between serum concentrations of persistent organic pollutants (POPs), especially organochlorine (OC) pesticides or nondioxin-like polychlorinated biphenyls (PCBs), and prevalence of diabetes in a U.S population with background exposure to POPs. Here, we investigated POPs and insulin resistance, a frequent pathogenic precursor of type 2 diabetes. RESEARCH DESIGN AND METHODS - Serum POPs and homeostasis model assessment of insulin resistance (HOMA-IR) were investigated cross-sectionally in 749 nondiabetic participants aged ≥20 years. Nineteen POPs in five subclasses were selected, detectable in ≥60% of participants. RESULTS - Among subclasses, OC pesticides were most strongly associated with HOMA-IR. Adjusted geometric means of HOMA were 3.27, 3.36, 3.48, and 3.85 (P for trend <0.01) across quartiles of OC pesticides. The relationship strengthened with increasing HOMA-IR percentile: adjusted odds ratios comparing the highest versus lowest POPs quartile were 1.8 for being ≥50th percentile of HOMA-IR, 4.4 for being ≥75th percentile, and 7.5 for being ≥90th percentile. Associations with elevated HOMA-IR appeared to be specific to oxychlordane and trans-nonachlor but also were found for two nondioxin-like PCBs. No HOMA-IR associations were seen in the other three POP subclasses. The association between OC pesticides and HOMA-IR tended to strengthen as waist circumference increased, with no apparent association in the lowest quartile of OC pesticide concentrations. CONCLUSIONS - These findings, coupled with those concerning diabetes prevalence, suggest that OC pesticides and nondioxin-like PCBs may be associated with type 2 diabetes risk by increasing insulin resistance, and POPs may interact with obesity to increase the risk of type 2 diabetes.