Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer. Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls. Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110,110 to 800, and >800 μg/L were 1.00,1.88 [95% confidence interval (CI), 0.96-3.71], and 5.24 (3.05-9.00; Ptrend < 0.001) for lung cancer, and 1.00,2.94 (1.29-6.70), and 8.11 (4.31-15.25; Ptrend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed. Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure. Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease.