A case of Sjögren's syndrome with the sicca complex is presented which was associated with persistently low or absent C4 levels, high levels of circulating immune complexes and abnormal reticuloendothelial clearance of damaged or IgG antibody sensitized autologous red blood cells (RBCs). Investigation of normal relatives of the patient revealed low C4 levels and abnormal reticuloendothelial clearance of damaged or sensitized RBCs. HLA, A, B, DR typing revealed a high incidence of the HLA B8, DR3 haplotype and of homozygous null alleles at the C4A locus in the family members. These results suggest that the C4 deficiency and the abnormal reticuloendothelial function in the patient was in part genetically determined and may have predisposed to the development of Sjögren's syndrome. These findings serve to emphasize the possible importance of abnormal macrophage function in the pathogenesis of Sjögren's syndrome and suggest that further investigation of these aspects may increase understanding of this disease.