To determine the potential utility of antigen-specific immune complex analysis, we developed a competitive enzyme-linked immunosorbent assay utilizing polyclonal human antibody to detect tumor-associated antigen-specific immune complexes. Sera from 10 normal volunteers and 19 patients with recurrent melanoma were studied. Patients with recurrent melanoma had a mean +/- SD percent inhibition of 27.6% +/- 29.8% in contrast to normal individuals with a mean value of 8.4% +/- 17.8%. A monoclonal antibody (MAb JSI) was developed following immunization with a partially purified antigen. Utilizing MAb JSI, we developed a "sandwich" enzyme-linked immunosorbent assay and studied sera from 45 normal volunteers and 44 patients with cancer with recurrent melanoma. Results were expressed as a percent maximum binding of a positive control. The mean +/- SD percent maximum binding for normal subjects was 4.9% +/- 7.7% in contrast to sera from patients with melanoma who had a mean of 38.3% +/- 33.3%. Serial analysis of four patients with melanoma with tumor-associated antigen-specific immune complexes demonstrated the presence of tumor-associated antigen-specific immune complexes up to 12 years prior to clinical recurrence.