© 2014 The Authors. Background: Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstratethat arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced veryhigh concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958until an arsenic removal plant was installed in 1970.Methods:Weinvestigated breast cancermortality from1950 to 2010 amongwomen in Region II compared to RegionV, which had lowarsenicwater concentrations. Weconducted studies on human breast cancer cell lines andcompared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies. Findings: Before 1958, breast cancer mortality rates were similar, but in 1958-1970 the rates in Region II werehalf those in Region V (rate ratio RR= 0.51, 95% CI 0.40-0.66;p < 0.0001). Women under the age of 60 experienceda 70% reduction in breast cancer mortality during 1965-1970 (RR = 0.30, 0.17-0.54; p < 0.0001). Breastcancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurredin people in Region II. Interpretation: We found biologically plausible major reductions in breast cancermortality during high exposureto inorganic arsenic in drinking waterwhich could not be attributed to bias or confounding. Werecommend clinicaltrial assessment of inorganic arsenic in the treatment of advanced breast cancer.