Nephropathy is an established untoward event associated with intravascular administration of conventional high-osmolality contrast media (HOM). It has not been shown previously that lower-osmolality contrast media (LOM) are less nephrotoxic in a clinical setting. We evaluate the ability to replace HOM with LOM (in lower-extremity angiography) to reduce the incidence of nephropathy. We use multiple definitions for contrast-induced nephropathy (six different magnitudes of rise of serum levels of creatinine or blood urea nitrogen in various periods). The incidences of nephrotoxic effects with LOM vs HOM in patients with presumed risk factors, including preexisting renal insufficiency and diabetes, are evaluated also. When all patients are considered, the incidence of contrast-induced nephropathy for LOM vs HOM (defined as an increase in serum creatinine level greater than 0.3 mg/dl and greater than 20% on day 1, 2, or 3 and on day 5, 6, or 7, is 7% vs 26% (p = .001). When only patients with preangiography azotemia are considered, the incidence of contrast-induced nephropathy for LOM vs HOM is 10% vs 41% (p = .017); for diabetic patients, regardless of preangiography creatinine level, the incidence is 10% vs 31% (p = .012). Although contrast-induced nephropathy may develop even in a patient with no risk factors who receives LOM, LOM is associated with a decreased incidence of this condition, to various degrees, depending on the presence of risk factors.