Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) decrease serum cholesterol. Dyslipidemia is believed to be associated with the development of renal dysfunction. It was postulated that statins may reduce the development of renal dysfunction. The effect of statin use on the development of renal dysfunction in 197,551 patients (Department of Veterans Affairs, Veterans Integrated Service Network 16 [VISN16] database) was examined. Of these patients, 29.5% (58,332 patients) were statin users and 70.5% (139,219 patients) were not. Development of renal dysfunction was defined as doubling of baseline creatinine or increase in serum creatinine > or =0.5 mg/dl from the first to last measurement with a minimum of 90 days in between. During 3.1 years of follow-up, 3.4% of patients developed renal dysfunction. After adjustment for demographics, diabetes mellitus, smoking, hypertension, and other medications (mainly angiotensin-converting enzyme inhibitors, calcium channel blockers, and aspirin), use of statins decreased the odds of developing renal dysfunction by 13% (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82 to 0.92, p <0.0001). The beneficial effect of statins appeared to be independent of the decrease in cholesterol. Other variables that affected the development of renal dysfunction were age (OR 1.04, 95% CI 1.03 to 1.04, p <0.0001), diabetes (OR 1.77, 95% CI 1.68 to 1.86, p <0.0001), hypertension (OR 1.11, 95% CI 1.02 to 1.2, p = 0.0153), and smoking (OR 1.12, 95% CI 1.02 to 1.24, p = 0.0244). In conclusion, statin use may retard the development of renal dysfunction. The beneficial effect of statins in preventing the development of renal dysfunction appears to be independent of their lipid-lowering effect.