Rhenium-186 based radioimmunotherapy (RIT) may have potential for the treatment of minimal residual disease in patients with squamous cell carcinoma of head and neck (HNSCC). In an effort to enhance the efficacy of RIT, we evaluated the combination of RIT and anti-epidermal growth factor receptor (EGFR) therapy in nude mice bearing established HNSCC s.c. xenografts. For this purpose we used the EGFR-blocking monoclonal antibody (MAb) 425. Treatment of HNSCC-bearing mice with the combination of a single administration of 200 microCi 186Re-labeled MAb U36 as well as 1.1 mg unlabeled MAb 425 showed an enhanced efficacy in comparison to the single treatments. When 500 microCi 186Re-labeled MAb U36 were administered, all tumors eventually regressed completely. The combination of this RIT treatment with multiple injections of MAb 425 significantly increased the rate of tumor regression. Although RIT with 186Re-labeled MAbs appears to be very efficient on HNSCC xenografts, the combination with anti-EGFR MAb 425 may enhance the efficacy.