The objectives of this study were to (1) examine the relationship between total trihalomethanes (TTHM) levels in public water supplies and death attributed to colon cancer and (2) determine whether magnesium (Mg) levels in drinking water modify the effects of TTHM on risk of colon cancer development. A matched case-control study was used to investigate the relationship between the risk of death attributed to colon cancer and exposure to total trihalomethanes (TTHM) in drinking water in 53 municipalities in Taiwan. All colon cancer deaths of the 53 municipalities from 1998 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 cancer cases by gender, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each cancer case. Data on TTHM levels in drinking water were collected from Taiwan Environmental Protection Administration. Information on the levels of Mg in drinking water was obtained from the Taiwan Water Supply Corporation. The municipality of residence for cancer cases and controls was presumed to be the source of the subject's TTHM and Mg exposure via drinking water. Relative to individuals whose TTHM exposure levels were <4.9 ppb, the adjusted odds ration (OR) (with 95% confidence interval [CI]) for colon cancer was 1.14 (1.01-1.28) for individuals who had resided in municipalities served by drinking water with a TTHM exposure≥4.9 ppb. Evidence of an interaction between drinking-water TTHM and Mg intake via drinking water was noted. This is the first study to report an effect modification by Mg intake from drinking water in association between TTHM exposure and risk of colon cancer occurrence. Better knowledge of this modifying factor will help in public policymaking and setting health standards.