To determine the frequency of and risk factors for adverse reactions to high-osmolality contrast media, the authors prospectively studied hospitalized patients undergoing cardiac catheterization. The authors also studied patients undergoing peripheral angiography and contrast material-enhanced computed tomography (CT) of the head or body who met at least one of the following criteria thought to increase the risk of adverse reactions: age of more than 60 years, diabetes, renal or liver disease, concurrent nephrotoxic drug use, or a history of allergic reactions (n = 795). Criteria were defined and used to group adverse reactions into three classes of clinical severity. Overall, class I (mild), class II (moderate), and class III (severe) reactions occurred in 362 (45%), 44 (5.5%), and three (0.4%) patients, respectively. Class II reactions were relatively common (25%) in patients undergoing cardiac catheterization yet were uncommon (2%) in patients undergoing the other three procedures. Nephrotoxicity occurred in 18 of 651 patients who had follow-up creatinine levels obtained at 48-72 hours. With multivariate regression analysis, the only risk factor (P less than .05) for combined class II and III reactions was diabetes. Diabetes, furosemide use, and a history of atopy (odds ratio = 2.8) were associated with nephrotoxicity (P less than .05). Underlying renal insufficiency was not a risk factor for nephrotoxicity.