Patients with drug-related lupus erythematosus produce antibodies to nuclear histones which can be detected by a three-step indirect immunofluorescence technique. Procainamide-related antinuclear antibodies were detected by this technique, but hydralazine-related antinuclear antibodies were not. Certain evidence suggests that antibodies induced by the two drugs are reactive with different subclasses of histones. Hydralazine was shown to interact with a soluble DNA-histone complex, and the resulting interaction rendered the histone moiety resistant to trypsin digestion. This mechanism may help to maintain DNA-histone complexes in a potentially immunogenic form and result in the production of autoantibodies.