A large-scale (337,647 cases), nationwide comparative clinical study in Japan on adverse drug reactions (ADRs) to high-osmolar ionic contrast media and low-osmolar nonionic contrast media was performed prospectively. Ionic contrast media were administered in 169,284 cases (50.1%) and nonionic contrast media in 168,363 cases (49.9%). The overall prevalence of ADRs was 12.66% in the ionic contrast media group and 3.13% in the nonionic contrast media group. Severe ADRs occurred in 0.22% of the ionic and 0.04% of the nonionic contrast media examinations. One death occurred in each group, but a causal relationship to the contrast medium could not be established. It is concluded that nonionic contrast media significantly reduce the frequency of severe and potentially life-threatening ADRs to contrast media at all levels of risk and that use of these media represents the most effective means of increasing the safety of contrast media examinations.