Serum antibody reactivity to squamous cell carcinoma of the head and neck (SCCHN) was evaluated in 41 autologous serum-tumor cell line combinations using the protein A hemadsorption assay. Autologous antibody reactivity (median titer of 1:4) was detected in sera from 24 of the patients tested. In 10 cases autologous antibody reactivity could be detected only in undiluted serum precluding further analysis. Analysis of higher titer sera from one patient revealed antibodies that define an antigen expressed on autologous tumor cells cultured from both the primary tumor (UM-SCC-17A) and from a metastasis (UM-SCC-17B). Absorption analysis showed that this antigen was also expressed on 6 of 10 allogeneic SCCHN cell lines but not on autologous fibroblasts or on allogeneic melanoma cell lines. Due to the low titer of autologous antibody reactivity in most sera, we sought to determine if dissociation of immune complexes through acidification and ultrafiltration of serum might enhance detectable antibody reactivity as has been done in previous studies in melanoma. Twelve serum samples from eight patients were subjected to acid dissociation and ultrafiltration (AD-U). Only six of the untreated sera had detectable antibody reactivity against the autologous SCCHN cell line whereas following AD-U all 12 sera had enhanced IgG reactivity against autologous SCCHN. Specificity analysis of one serum sample after dissociation revealed that the antibody detected an antigen common to SCCHN cell lines as well as melanoma, glioma, renal, and colon carcinoma cell lines. Circulating immune complexes may provide a reservoir of antibody with potential diagnostic and therapeutic applications.