HMG-coA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use. However, little is known about the association between long-term statin use and incidence of most types of cancers. We examined the association between long-term use of cholesterol-lowering drugs, predominantly statins, and the incidence of ten common cancers, as well as overall cancer incidence, among 133,255 participants (60,059 men and 73,196 women) in the Cancer Prevention Study II Nutrition Cohort during the period from 1997 to 2007. Multivariate Cox proportional hazards regression was used to estimate relative risks (RR). Current use status and duration of use were updated during follow-up using information from biennial follow-up questionnaires. Current use of cholesterol-lowering drugs for five or more years was not associated with overall cancer incidence (RR = 0.97, 95% CI = 0.92-1.03), or incidence of prostate, breast, colorectal, lung, bladder, renal cell, or pancreatic cancer but was associated with lower risk of melanoma (RR = 0.79, 95% CI = 0.66-0.96), endometrial cancer (RR = 0.65, 95% CI = 0.45-0.94), and non-Hodgkin lymphoma (NHL; RR = 0.74, 95% CI = 0.62-0.89). These results suggest that long-term use of statins is unlikely to substantially increase or decrease overall cancer risk. However, associations between long-term statin use and risk of endometrial cancer, melanoma, and NHL deserve further investigation.