Before CDDP was clinically used, combination chemotherapy regimens like BLM + MMC, VCR + MTX-LV + BLM, VCR + MTX-LV + BLM + MMC had been used for recurrent tumors of the head and neck. In a phase II study with CDDP, we experienced two patients with long-term survival (12, 15+) who were treated with CDDP as a second-line chemotherapy for recurrent tumors. Cisplatin was evaluated as a potentially curative agent. After that, CDDP based regimens have been used as neo-adjuvant setting (first-line chemotherapy). So it became quite difficult to make up a second-line chemotherapy since CDDP based regimens have been used as the first-line chemotherapy. We conducted basic research on second-line chemotherapy for recurrent head and neck cancer: (1) cross-resistance studies on head and neck cancer cell lines resistant to CDDP, 5-FU, MTX and BLM; (2) second line chemotherapy for CDDP + PEP combination chemotherapy, which was developed by us, in human KB cell line; and (3) effects of etoposide plus mitomycin C on head and neck squamous cell carcinoma in monolayer and multicellular tumor spheroid. Based on our long-term experience with chemotherapy for head and neck cancer, and the results of the above-mentioned basic research, we established a policy to select second-line chemotherapy for recurrent head and neck cancer, especially in cases previously treated with chemotherapy.