The IgG subclasses of anti-tetanus toxoid (anti-TT) antibodies were quantitated in normal sera and sera from patients with rheumatic disease. Detection relied on a set of four mouse monoclonal antibodies, each of which showed specificity for the respective isotype, independent of gamma-chain allotype or light chain class of the human antibody. Approximately 90% of the total anti-TT activity in normal adults and patients with Sjogren's syndrome was IgG1. In addition, IgG4 antibodies were detected in one-half the samples, but IgG2 and IgG3 antibodies were observed in only two out of 36 sera. However, antibodies elicited in children immunized with TT were exclusively IgG1 and IgG3, with IgG4 antibodies detectable only at birth (presumably due to transplacental passage of antibody) in three of 12 children. In contrast to normal adults, patients with systemic lupus erythematosus (SLE) and drug-induced autoimmunity (DIA) had a more promiscuous isotype profile. IgG2 and/or IgG3 anti-TT antibodies were detected in 13 of 22 SLE patients and IgG3 antibodies in six of 11 patients with DIA. IgG4 anti-TT antibodies were predominant in seven of these 33 patients. These findings suggest that IgG isotypes may depend on the frequency of the stimulus, but global alterations in immunologic status as reflected in systemic autoimmune disease may override the homeostatic mechanisms that control isotype restriction.