Cities in northern Chile had arsenic concentrations of 860 microg/liter in drinking water in the period 1958-1970. Concentrations have since been reduced to 40 microg/liter. We investigated the relation between lung cancer and arsenic in drinking water in northern Chile in a case-control study involving patients diagnosed with lung cancer between 1994 and 1996 and frequency-matched hospital controls. The study identified 152 lung cancer cases and 419 controls. Participants were interviewed regarding drinking water sources, cigarette smoking, and other variables. Logistic regression analysis revealed a clear trend in lung cancer odds ratios and 95% confidence intervals (CIs) with increasing concentration of arsenic in drinking water, as follows: 1, 1.6 (95% CI = 0.5-5.3), 3.9 (95% CI = 1.2-12.3), 5.2 (95% CI = 2.3-11.7), and 8.9 (95% CI = 4.0-19.6), for arsenic concentrations ranging from less than 10 microg/liter to a 65-year average concentration of 200-400 microg/liter. There was evidence of synergy between cigarette smoking and ingestion of arsenic in drinking water; the odds ratio for lung cancer was 32.0 (95% CI = 7.2-198.0) among smokers exposed to more than 200 microg/liter of arsenic in drinking water (lifetime average) compared with nonsmokers exposed to less than 50 microg/liter. This study provides strong evidence that ingestion of inorganic arsenic is associated with human lung cancer.