OBJECTIVE Recommendations to restrict low-osmolality contrast to high-risk patients having cardiac angiography have been challenged because of safety and uncertainty about selection criteria. The authors document frequency and severity of adverse events with diagnostic cardiac angiography under the influence of guidelines for selective use of low-osmolality contrast in high-risk patients and refine high-risk criteria. METHODS Subjects of this prospective cohort study were 7,448 unselected patients having diagnostic cardiac angiography in St. John's, Newfoundland or Ottawa, Ontario. Measures included prespecified risk factors, procedure, contrast, and adverse events such as death within 24 hours, myocardial infarction, stroke, arrhythmias, hypotension, and anaphylactoid reactions. RESULTS Patients were similar at both sites. Fourteen point two percent received low-osmolality nonionic agents in St. John's. Thirty-four point one percent received low-osmolality (mostly ionic) media in Ottawa. Overall adverse event rates were similar at both sites: death, 0.07%; myocardial infarction or stroke, 0.03%; moderate events, 2%; and mild events, 16.8%. Event rates were low in those given high-osmolality media: death, 0.02%; myocardial infarction or stroke, 0.24%; moderate events, 1.6%; and mild events, 18%. The risk with cardiogenic shock and prior severe reaction to contrast could not be examined, but otherwise only current heart failure and markers of recent ischemia were associated with events after high-osmolality media. CONCLUSIONS Clinicians, using guidelines, can identify high-risk patients and should be able to safely limit use of low-osmolality media to them.