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The risk of skin lesions associated with arsenic exposure from drinking water in Bangladesh is considerably greater in men than in women.Using baseline data from 11,062 cohort members in the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh, we performed a cross-sectional analysis to evaluate whether the association between arsenic exposure from drinking water and the risk of skin lesions is modified by tobacco smoking, excessive sunlight, the use of fertilizer, and the use of pesticides. A time-weighted well arsenic concentration was estimated for each participant by incorporating history of well use. Relative excess risk for interaction (RERI) and its 95% confidence intervals (CIs) were estimated using adjusted prevalence odds ratios.We observed a synergistic effect between the highest level of arsenic exposure (>113 μg/L) and tobacco smoking on risk of skin lesions in men (RERI = 1.5 [95% CI = 0.3 to 2.7] overall and 1.7 [0.2 to 3.4] for the subpopulation with longer-term arsenic exposure). We also observed suggestive synergistic effects between higher levels (28.1–113.0 μg/L and 113.1–864.0 μg/L) of arsenic exposure and fertilizer use in men (RERI = 1.0 [−0.2 to 2.2] and 1.3 [−0.2 to 2.9] respectively). Furthermore, the risk of skin lesions associated with any given level of arsenic exposure was greater in men with excessive sun exposure. The patterns of effect estimates in women indicate similar-but-weaker interaction effects of arsenic exposure with tobacco smoking and fertilizer use.These findings help explain why the risk of arsenic-related skin lesions was much greater in men than in women in Bangladesh. Because most arsenic-induced skin cancers arise from these skin lesions, treatment and remediation plans should take into consideration these etiologic cofactors.