Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been linked with potential chemopreventive effects; however, the data are conflicting. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry for the period 1989-2002. In a study population of 334,754 county residents, we compared overall and site-specific cancer incidence among 12,251 statin users (≥2 prescriptions) with cancer incidence among nonusers and users of other lipid-lowering drugs (n = 1,257). Statistical analyses were based on age-standardization and Poisson regression analysis, adjusting for age, gender, calendar period and use of NSAIDs, hormone replacement therapy and cardiovascular drugs. We identified 398 cancer cases among statin users during a mean follow-up period of 3.3 years (range 0-14 years). The age- and gender-standardized incidence rates of cancer overall were 596 per 100,000 person-years among statin users, 645 per 100,000 person-years among nonusers and 795 per 100,000 person-years among users of other lipid-lowering drugs. Adjusted rate ratios for cancer overall among statin users were 0.86 (95% CI, 0.78-0.95) compared to nonusers and 0.73 (95% CI, 0.55-0.98) compared to users of other lipid-lowering drugs. No significantly increased or decreased rate ratios were observed for any of the studied site-specific cancers (liver, colorectum, lung, breast, prostate, female genital organs and lymphatic and haematopoietic tissue), but most estimates tended to be less than 1.0. Stratification by duration of follow-up or number of prescriptions revealed no clear trends. In summary, individuals prescribed statins experienced a slightly reduced cancer incidence compared to population controls of nonusers and users of other lipid-lowering drugs. Larger and longer-term studies are needed to determine the potentially protective effect of statin use on cancer development.