The comparative frequency of and risk factors for nephrotoxicity with low-osmolality contrast medium (LOM) versus high-osmolality contrast medium (HOM) were investigated. A randomized, double-blind clinical trial was conducted in patients undergoing diagnostic angiocardiography (n = 430) or contrast material-enhanced body computed tomography (CT) (n = 499). Nephrotoxicity was defined as an increase in serum creatinine level that was greater than both 33% and 0.4 mg/dL (40 mumols/L) above the baseline level within 48 hours after the radiologic procedure. The frequency of nephrotoxicity was similar in patients who received LOM versus those who received HOM: 13 of 479 (2.7%) versus 13 of 450 (2.9%), respectively (P = .87), overall; 4.4% versus 4.0% in angiocardiography patients (P = .84); and 1.2% versus 2.0% in body CT patients (P = .35). Factors associated (P less than .05) with increased risk of nephrotoxicity were insulin-dependent diabetes, baseline serum creatinine level greater than 1.5 mg/dL (130 mumols/L), concurrent use of furosemide, and angiocardiographic examination. Patients who have preexisting renal insufficiency may be at higher risk for nephrotoxicity with HOM than with LOM.