IgG anti-histone antibodies were detected by indirect immunofluorescence in 6 out of 70 sera from rheumatoid arthritis with antinuclear factors, in 1 out of 13 from scleroderma, in 14 out of 25 from spontaneous systemic lupus erythematosus (SLE) and in 11 out of 14 from drug induced lupus. Rheumatoid arthritis patients with IgG anti-histone antibodies were characterized by the severity of joint involvement and by the high frequency of extraarticular features of the disease. SLE patients with anti-histone antibodies only differed from patients without such antibodies by a higher frequency of Raynaud phenomenon (p less than 0.05). Longitudinal studies of spontaneous SLE showed that IgG anti-histone antibodies correlated with disease activity (p less than 0.001). A significant correlation was demonstrated between anti-histone IgGs and anti-ds-DNA antibodies assessed by the Farr binding assay (p less than 0.0001). IgG anti-histone antibodies were rarely found in sera from patients with drug induced antinuclear antibodies without symptoms of SLE (1 out of 6 sera). In drug induced lupus, IgG anti-histone antibodies were found in the absence of high titers of anti-ds-DNA antibodies, and this discrepancy appeared to suggest the diagnosis of drug induced lupus. Finally, anti-histone antibodies were present in 5 out of 7 sera from acebutolol induced lupus.