Type 2 diabetes mellitus (T2DM) disproportionately affects Indigenous populations. It is possible that exposure to complex mixtures of environmental contaminants contribute to T2DM development. This study examined the association between complex environmental contaminant mixtures and T2DM among Canadian Indigenous communities from the
Eeyou Istcheeterritory, Quebec, Canada. Using data from the cross-sectional Multi-Community Environment-and-Health Study (2005–2009) Principal Component Analysis (PCA) was used to reduce the dimensionality of the following contaminants: 9-polychlorinated biphenyl congeners; 7-organic pesticides; and 4-metal/metalloids. Following this data reduction technique, we estimated T2DM prevalence ratios (PR) and 95% confidence intervals using modified Poisson regression with robust error variance across derived principal components, adjusting for a prioricovariates. For both First Nation adult males (n = 303) and females (n = 419), factor loadings showed dichlorodiphenyltrichloroethane (DDT) and lead (Pb) highly loaded on the second principal component (PC) axis: DDT negatively loaded, and Pb positively loaded. T2DM was significantly associated with PC-2 across all adjusted models. Because PCA produces orthogonal axes, increasing PC-2 scores in the fully adjusted model for females and males showed (PR = 0.84; 95% CI 0.72, 0.98) and (PR = 0.78; 95% CI 0.62, 0.98), respectively. This cross-sectional study suggests that our observed association with T2DM is the result of DDT, and less likely the result of Pb exposure. Further, detectable levels of DDT among individuals may possibly contribute to disease etiology.