BACKGROUND Consumption of drinking water with high levels of inorganic arsenic (over 500 μg/L) has been associated with type II diabetes mellitus (DM), but previous studies have been inconclusive about risks at lower levels (<100 μg/L). We present a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of DM. METHODS This case-cohort study included 141 cases of DM diagnosed between 1984 and 1998 as part of the prospective San Luis Valley Diabetes Study. A comparison sub-cohort of 488 participants was randomly sampled from 936 eligible participants who were disease free at baseline. Individual lifetime arsenic exposure estimates were determined using a methodology that incorporates the use of a structured interview to determine lifetime residence and employment history, geospatial modeling of arsenic concentrations in drinking water, and urine arsenic concentrations. A Cox proportional hazards model with known DM risk factors as time-dependent covariates was used to assess the association between lifetime exposure to inorganic arsenic in drinking water and incident DM. RESULTS Our findings show a significant association between inorganic arsenic exposure and DM risk (hazard ratio [HR]=1.27, 95%=1.01, 1.59 per 15 μg/L) while adjusting for ethnicity and time varying covariates age, body mass index and physical activity level. CONCLUSIONS Exposure to low-level inorganic arsenic in drinking water is associated with increased risk for type II DM in this population based on a comprehensive lifetime exposure assessment.