The objective of this study was to explore whether calcium (Ca) levels in drinking water modified the effects of nitrate on colon cancer risk. A matched case–control study was used to investigate the relationship between the risk of death from colon cancer and exposure to nitrate in drinking water in Taiwan. All colon cancer deaths of Taiwan residents from 2003 through 2007 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to the cases by gender, year of birth and year of death. Information on the levels of nitrate-nitrogen (NO3-N) and Ca in drinking water have been collected from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cases and controls was assumed to be the source of the subject's NO3-N and Ca exposure via drinking water. We observed evidence of an interaction between drinking water NO3-N and Ca intake via drinking water. This is the first study to report effect modification by Ca intake from drinking water on the association between NO3-N exposure and risk of colon cancer mortality.