Arsenic in drinking water is known to be a cause of lung, bladder, and skin cancer, and some studies report cardiovascular disease effects. The authors investigated mortality from 1950 to 2000 in the arsenic-exposed region II of Chile (population: 477,000 in 2000) in comparison with the unexposed region V. Increased risks were found for acute myocardial infarction (AMI), with mortality rate ratios of 1.48 for men (95% confidence interval (CI): 1.37, 1.59; p < 0.001) and 1.26 for women (95% CI: 1.14, 1.40; p < 0.001) during the high-exposure period in region II from 1958 to 1970. The highest rate ratios were for young adult men aged 30–49 years who were born during the high-exposure period with probable exposure in utero and in early childhood (rate ratio = 3.23, 95% CI: 2.79, 3.75; p < 0.001). Compared with lung and bladder cancer, AMI mortality was the predominant cause of excess deaths during and immediately after the high-exposure period. Ten years after reduction of exposures, AMI mortality had decreased, and longer latency excess deaths from lung and bladder cancer predominated. With these three causes of death combined, increased mortality peaked in 1991–1995, with estimated excess deaths related to arsenic exposure constituting 10.9% of all deaths among men and 4.0% among women.