Abnormal growths were observed on the lips and in the oral cavities of 2- and 3-year-old Chinook salmon (Oncorhynchus tshawytscha) maintained in one freshwater and one saltwater captive fish-rearing facility in the Columbia River (Pacific Northwest). Initially presenting as bilaterally symmetrical, red, irregular plaques on oral mucosal surfaces, the lesions developed progressively into large, disfiguring masses. Of the 502 natural parr collected for captive broodstock, 432 (86%) displayed these tumors, whereas cohort salmon (i.e., same year classes) in these same facilities remained unaffected. Morphologically similar neoplasms were collected occasionally from adult Chinook salmon that had returned to their natal streams. Histologic features of the tumors suggested that they were derived from the portion of dental lamina destined to form tooth root sulci; therefore, these neoplasms were diagnosed as ameloblastomas. The lesions also resembled archived specimens of Chinook salmon oral tumors, which had been described decades earlier. Etiologic investigations performed during the current outbreak included bacteriologic, virologic, genetic, ultrastructural analyses, and cohabitation exposure studies. Results of these efforts did not indicate an obvious genetic basis for this syndrome, attempts to isolate potentially causative viruses or bacteria were negative, and disease transmission to naïve fish was unsuccessful. A few intracytoplasmic hexagonal structures, possibly consistent with viral particles (approximately 100 nm), were observed ultrastructurally in a tumor cell from 1 of 6 specimens submitted for transmission electron microscopy. Although the presence of these particles does not constitute sufficient evidence for causality, an infectious or multifactorial etiology seems plausible.