Several studies have suggested that systemic hypertension as a disease or its therapy could increase the risk for malignancies. Diuretics reduce cardiovascular morbidity and mortality and constitute a cornerstone in the antihypertensive arsenal. To analyze the relation between diuretic therapy and the risk of malignancies, we conducted a comprehensive review of pertinent previous publications by searching the MEDLINE database for related articles in all languages published between January 1966 and April 1998. Within the past decade, we found 9 case control studies and 3 cohort studies in which the relation between diuretic use and renal cell carcinoma was examined. In the case control studies, the odds ratio of renal cell carcinoma occurring in patients treated with diuretics averaged 1.55 with a 95% confidence interval of 1.42 to 1.71 (p <0.00001) compared with nonusers of diuretics. In the 3 cohort studies of 1,226,229 patients, diuretic therapy was associated with a more than twofold risk of renal cell carcinoma when compared with patients not on diuretics. In 1 cohort study, and in the 7 case control studies in which the effects of gender were reported, women had a higher odds ratio (2.01, confidence interval 1.56 to 2.67) than men (1.69 confidence interval 1.34 to 2.13). Thus, cumulative evidence, possibly stronger in women than in men, suggests that the long-term use of diuretics may be associated with renal cell carcinoma. Although diuretics remain the best documented drug class to reduce morbidity and mortality in systemic hypertension, our data suggest a need for continued vigilance to assess the risk-benefit ratio of all drugs used for long-term therapy of cardiovascular disorders.