The etiology of multiple primary cancers has not been clearly elucidated, although some pathogenic factors are known. The studies reported here include 796 patients who, between January 1970 and March 1989, presented with a carcinoma of the upper aerodigestive system. The charts of 687 patients were analyzed retrospectively; 109 patients were studied prospectively by systematic pretherapeutic panendoscopy. Multiple primary cancers were found in 76 cases (9.5%), 33 patients had synchronous cancers, and 43 had metachronous cancers. In the prospective study, the incidence of multiple cancers was higher (13.7%) than in the retrospective group (8.8%). Synchronous primaries were more frequent in the prospective study (8.2%) than in the retrospective analysis (3.4%). Second primaries were mostly found in the esophagus, the hypopharynx, the buccal cavity, and the lung. The authors also examined whether the anatomic location of the second primary cancer can be related to the site of the first. The five-year survival rate among patients with synchronous cancers (18%) was lower than among patients with metachronous cancers (41%). The prognosis for synchronous cancers deteriorates if the planned treatment has to be modified following the discovery of a second primary. Systematic pretherapeutic panendoscopy should be used to help detect early asymptomatic second primaries which might be missed during clinical examination.