Although use of oral contraceptives (OCs) is common, their influence on carcinogenesis is not fully understood. We used Cox proportional hazards models to examine OC use (never/<1 year (referent), 1-4, 5-9, ≥10 years) and development of incident cancers across body sites within the same base population: women in the prospective National Institutes of Health-AARP Diet and Health Study (enrolled 1995-1996 and followed until 2011). Adjustment for confounding varied by outcome; all models accounted for age, race, body mass index, and smoking status, and included at least 100,000 women. Any OC use conferred a 3% reduction in the risk for any cancer (hazard ratio = 0.97, 95% confidence interval: 0.95, 0.99). Expected risk reductions that strengthened with duration of use were identified for ovarian and endometrial cancers and were suggested for kidney cancer (all P for trend < 0.05). Non-Hodgkin lymphoma risk (hazard ratio = 0.79, 95% confidence interval: 0.64, 0.97) was reduced with 10 or more years of OC use. There was a 37% reduced risk for bladder cancer and 46% increased risk for pancreatic cancer among long-term OC users who were 60 years of age or younger at baseline. OC use did not influence risks for most other cancers evaluated. Given the high prevalence of use and changing formulations, additional studies are warranted to fully understand the chemopreventive effects of these medications.