Arsenic has been well documented as the major risk factor for blackfoot disease (BFD), a unique peripheral vascular disease that was endemic to the southwestern coast of Taiwan, where residents consumed high-arsenic artesian well water for more than 50 yr. Chronic arsenic exposure was also reported to be associated with increased mortality attributed to colon cancer. A tap-water supply system was implemented in the early 1960s in the BFD-endemic areas. Artesian well water was no longer used for drinking and cooking after the mid-1970s. The objective of this study was to determine whether colon cancer mortality decreased after the improvement of the drinking-water supply system through elimination of arsenic ingestion from artesian well water. Standardized mortality ratios (SMRs) for colon cancer were calculated for the BFD-endemic area for the years 1971-2006. Results showed that mortality due to colon cancer declined in males, but not in females, gradually after the improvement of drinking-water supply system. Based on the reversibility criterion, the association between arsenic exposure and colon cancer incidence is likely to be causal for males but not females. The possibility that our results may be due to chance should be considered; however, gender-specific differences in arsenic metabolism may be a critical factor.