Calcium-channel blockers can alter apoptosis, a mechanism for destruction of cancer cells. We examined whether the long-term use of calcium-channel blockers is associated with an increased risk of cancer. Between 1988 and 1992 we carried out a prospective cohort study of 5052 people aged 71 years or more and who lived in three regions of Massachusetts, Iowa, and Connecticut USA. Those taking calcium-channel blockers (n = 451) were compared with all other participants (n = 4601). The incidence of cancer was assessed by survey of hospital discharge diagnoses and causes of death. These outcomes were validated by the cancer registry in the one region where it was available. Demographic variables, disability, cigarette smoking, alcohol consumption, blood pressure, body-mass index, use of other drugs, hospital admissions for other causes, and comorbidity were all assessed as possible confounding factors. The hazard ratio for cancer associated with calcium-channel blockers (1549 person-years, 47 events) compared with those not taking calcium-channel blockers (17225 person-years, 373 events) was 1.72 (95% CI 1.27-2.34, p = 0.0005), after adjustment for confounding factors. A significant dose-response gradient was found. Hazard ratios associated with verapamil, diltiazem, and nifedipine did not differ significantly from each other. The results remained unchanged in community-specific analyses. The association between calcium-channel blockers and cancer was found with most of the common cancers. Calcium-channel blockers were associated with a general increased risk of cancer in the study populations, which suggested a common mechanism. These observational findings should be confirmed by other studies.