Antinuclear antibodies develop in most patients who are given prolonged procainamide therapy, but clinical symptoms resembling those of lupus appear in only 15 to 20 percent of such persons. No objective marker for symptomatic procainamide-induced lupus has been described. However, IgG antibodies to the histone complex H2A-H2B have previously been reported in this disorder, and it has been suggested that antiguanosine antibodies may be a marker for major manifestations of procainamide-induced lupus. We therefore tested for these antibodies in 20 symptomatic and 31 asymptomatic patients treated with procainamide. Most of the symptomatic patients had multiple manifestations of drug-induced lupus; resolution of symptoms after the discontinuation of procainamide was required for inclusion in the symptomatic group. All 20 symptomatic patients had elevated IgG antibodies to H2A-H2B, in contrast to only 2 asymptomatic patients (P less than 0.001). This activity was absent in patients not treated with procainamide and in patients with lupus induced by hydralazine or quinidine. IgG antiguanosine was elevated as compared with normal controls in 13 of 20 symptomatic and 19 of 31 asymptomatic patients--a finding that did not distinguish between symptomatic and asymptomatic patients. We conclude that IgG antibodies to H2A-H2B are a sensitive and specific marker for procainamide-induced lupus. The striking correlation between antibodies to H2A-H2B and symptomatic disease suggests a possible association between this antibody and the underlying pathogenic events.