BACKGROUND: The objective of this population-based case-referent study in Matlab, Bangladesh, was to assess the susceptibility to arsenic-induced skin lesions by age and sex, in a population drinking water from As-contaminated tube wells. METHODS: Identification of As-related skin lesions was carried out in three steps: a) screening of the entire population > 4 years of age (n = 166,934) by trained field teams; b) diagnosis of suspected As-related cases by physicians; and c) confirmation by experts based on physicians' records and photographs. A total of 504 cases with skin lesions were confirmed. We randomly selected 2,201 referents from the Matlab health and demographic surveillance system; 1,955 were eligible, and 1,830 (94%) were available for participation in the study. Individual history of As exposure was based on information obtained during interviews and included all drinking-water sources used since 1970 and concentrations of As (assessed by atomic absorption spectrophotometry) in all the tube wells used. RESULTS: Cases had been exposed to As more than referents (average exposure since 1970: male cases, 200 microg/L; female cases, 211 microg/L; male referents, 143 microg/L; female referents, 155 microg/L). We found a dose-response relationship for both sexes (p < 0.001) and increased risk with increasing socioeconomic status. Males had a higher risk of obtaining skin lesions than females (odds ratio 10.9 vs. 5.78) in the highest average exposure quintile (p = 0.005). Start of As exposure (cumulative exposure) before 1 year of age was not associated with higher risk of obtaining skin lesions compared to start of As exposure later in life. CONCLUSIONS: The results demonstrate that males are more susceptible than females to develop skin lesions when exposed to As in water from tube wells.