To investigate whether circulating immune complexes can be used as a disease marker for assessment of the activity of Lyme disease and for monitoring patients response to treatment, we tested 104 sera from patients with different stages of Lyme disease using the C1q enzyme-linked immunosorbent assay (ELISA) and a modified Raji cell test. Among 62 sera of patients with clinically active disease 27 sera (43.5%) reacted positively in the C1q-ELISA and 21 sera (33.9%) positively in the Raji cell test. In contrast, serum circulating immune complexes were found in less than 10% of 42 sera after antibiotic treatment. Similar results were obtained by both tests in 35 cerebrospinal fluid samples from patients with neuroborreliosis. Most importantly, dot blot analysis revealed the presence of both Borrelia burgdorferi-specific antigen(s) and host-derived components in the isolated immune complexes from serum samples of patients with active Lyme disease. These results indicate that detection of circulating immune complexes may be an useful parameter for judging the activity of Lyme disease. Moreover, preliminary characterization of spirochete-specific immune complexes implies new pathophysiological aspects of Lyme disease.