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Association of urinary arsenic concentration with incident diabetes was examined in American Indians from Arizona who have a high prevalence of type 2 diabetes and were screened for diabetes between 1982 and 2007. The population resides where drinking water contains arsenic at concentrations above federally recommended limits. A total of 150 nondiabetic subjects aged >= 25 years who subsequently developed type 2 diabetes were matched by year of examination and sex to 150 controls who remained nondiabetic for >= 10 years. Total urinary arsenic concentration, adjusted for urinary creatinine level, ranged from 6.6 mu g/L to 123.1 mu g/L, and inorganic arsenic concentration ranged from 0.1 mu g/L to 36.0 mu g/L. In logistic regression models adjusted for age, sex, body mass index, and urinary creatinine level, the odds ratios for incident diabetes were 1.11 ( 95% confidence interval ( CI): 0.79, 1.57) and 1.16 ( 95% CI: 0.89, 1.53) for a 2-fold increase in total arsenic and inorganic arsenic, respectively. Categorical analyses suggested a positive relationship between quartiles of inorganic arsenic and incident diabetes ( P = 0.056); post-hoc comparison of quartiles 2-4 with quartile 1 revealed 2-fold higher odds of diabetes in the upper quartiles ( OR = 2.14, 95% CI: 1.19, 3.85). Modestly elevated exposure to inorganic arsenic may predict type 2 diabetes in American Indians. Larger studies that include measures of speciated arsenic are required for confirmation.