The distribution of human IgG subclasses among the glomerular deposits of 53 patients with glomerulonephritis was examined by immunofluorescence (IF) with subclass-specific monoclonal antibodies (Mab). A subclass restriction was observed in idiopathic membranous nephropathy (MN) with glomerular deposits predominantly containing IgG4 (81% of the studied biopsies) and IgG1 (75%). In de novo MN, occurring after transplantation, the restriction was markedly different, with a predominance of IgG1 (100%) and IgG2 (69%). In anti-glomerular basement membrane (a-GBM) nephritis the restriction was considerable with deposits containing almost exclusively IgG1 (91%) and IgG4 (73%). The same restriction was observed for circulating anti-GBM antibodies detected by indirect IF assay. By contrast IgG1, IgG2, and IgG3 deposits were identified in lupus proliferative glomerulonephritis. Serum IgG subclass levels were measured in 29 patients with idiopathic MN and a-GBM nephritis by an indirect competitive immunoenzymatic assay using Mab. Mean percentage of IgG2 serum level was significantly lower in patients. In spite of high variations from patient to patient, a serum IgG subclass imbalance was clearly present in 10 cases with low IgG2 and high IgG1 and IgG3 levels. The imbalance in these patients was not due to urinary loss since it was observed with a similar frequency in hypo- and normoimmunoglobulinemic patients. In 5 out of these 10 patients IgG2 levels were very low, analogous to those observed in selective IgG2 deficiency. Whether the important subclass restriction of glomerular IgG (in which patterns differed according to the type of glomerulonephritis) and the serum subclass imbalances were due to a clonally restricted antibody response to a particular antigen or to a host immune response defect, or both, remains to be elucidated.