Humoral immune responses in experimental African trypanosomiasis were assessed in rabbits infected with Trypanosoma rhodesiense. Immune complexes as measured by a Clq binding assay or a Clq solid-phase assay were detected by day 10 and increased progressively through day 28. Immune complexes analyzed by double diffusion in agar or enzyme immunoassay contained immunoglobulin M (IgM) and IgG consistently, and usually C3. In one serum, immune complexes contained trypanosomal antigens in addition to C3, IgG, and IgM. By sucrose density gradient ultracentrifugation Clq-binding immune complex-like materials were shown to contain IgG, IgM, and C3, sedimentating as intermediate (between 7S and 19S) or as higher-molecular-weight (greater than 19S) aggregates. Serum IgM and IgG antibodies to trypanosomes were measured by enzyme immunoassay. IgM antibodies were detected by day 7, rose to peak by day 14, and declined slowly thereafter. IgG antibodies were detected by day 14 and continued to rise through day 32. Total IgM and IgG measured by radial immunodiffusion paralleled the corresponding changes in antibody levels. Host immune responses, in part directed to trypanosomal antigens, produced circulating immune complexes containing bound C3; these may be deposited in tissue or may serve as a serological marker of immune complex-mediated tissue injury.