Elevated levels of macromolecules, within the peripheral blood of head and neck cancer patients, capable of binding the first component of complement (C1qBM) in vitro have prognostic implication. Namely, elevated levels of C1qBM have been associated with nonresponse to induction chemotherapy. In this investigation, a series of in vitro studies regarding the biological properties of C1qBM were combined with a longitudinal analysis of 112 previously untreated head and neck cancer patients. Our purpose was to shed light on the biological significance of this circulating macromolecule, a substance composed, in part, of IgG and IgM. A potential confounding influence of C1qBM with induction chemotherapy, which could contribute to observed prognostic findings, was negated by two in vitro observations: the macromolecule failed both to bind the chemotherapeutic agents cisplatin, bleomycin, and 5-fluorouracil and to impede the cytotoxic effect of these same drugs on a cultured human head and neck cancer cell line. The clinical relevance of C1qBM was reinforced by the observation that elevated levels predicted a high probability of death with disease (P = 0.005 by Cox's proportional hazards model). The prognostic implication was independent of the use of induction chemotherapy, i.e., patients with high C1qBM levels treated with multimodality therapy not composed of anticancer drugs did equally poorly. Thus, the prognostic significance of C1qBM in patients undergoing induction chemotherapy appears independent of drug effect and appears reflective of tumors that are more rapidly progressive and potentially less responsive to therapeutic intervention, including combinations of surgery, radiation, and/or chemotherapy.