We have developed a system in which antibody-dependent cellular cytotoxicity (ADCC) can be consistently demonstrated against squamous cell carcinoma (SCC) of the head and neck. Serum samples from patients with pemphigus vulgaris (PV) provided antibodies for ADCC. The effector cells were lymphocytes from the peripheral blood of healthy human donors. The SCC cell lines served as targets. Lysis of SCC, as measured by 51Cr release, was significantly enhanced by the presence of serum from patients with PV, but not by healthy human serum. Serum alone produced no target cell killing. Nonepithelial cell lines were not affected by the presence of PV antibodies. The results demonstrate that SCC is susceptible to ADCC. Thus, tumor-specific antibodies may have a role in the treatment of cancer of the head and neck. This system can serve as a positive control for further testing of ADCC against SCC.