A consecutive series of 22 patients with multiple synchronous squamous cell carcinomas of the upper aerodigestive tract was retrospectively reviewed. These patients were treated initially with cis-platinum combination chemotherapy before definitive locoregional therapy (surgery and/or radiation therapy). Sixteen of 21 patients had simultaneous head and neck and esophageal primaries, 3 patients had multiple synchronous head and neck primaries, 2 patients had head and neck (HN) and a bronchial epidermoid cancer, and 1 patient had simultaneous esophageal and bronchial carcinomas of epidermoid lineage. Sixteen (77%) of the 21 patients responded to chemotherapy in all the tumor sites evaluated, and a clinically complete response was obtained in 6 (29%). After definitive locoregional treatment, the complete local control rate was 68%, with 34 complete responses for 50 primary tumor sites in 21 patients. Twelve patients were free of disease after locoregional treatment. Six patients are still alive 27 to 57 months after complementary definitive locoregional treatment and a minimum follow-up of 27 months. Median survival for the overall group is 17 months. The response to chemotherapy is remarkable, which may be due to the small tumoral volume present in many of the cases (T1 to T2). Nevertheless, the present report stresses the importance of an aggressive combined therapeutic approach in this difficult clinical situation.