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Loss of autofluorescence as an early phenomenon associated with tissue degeneration seems to be promising for the diagnosis of oral cancer. The method seems to make visible early structural and biochemical alterations of the oral mucosa not always evident under direct inspection of the oral cavity.For this reason, the margins of the mucosal lesions usually appear wider compared with direct visualization. Actual extension of the potentially malignant lesions must be precisely perceived to avoid any underestimation of the tumor. In this study, 32 patients at risk for oral cancer underwent autofluorescence test. Of these patients, 12 (group A) experienced potentially malignant diseases. The other 20 patients (group B) were previously operated on for oral cancer. In addition, 13 patients showed loss of autofluorescence (8 patients from group A and 5 patients from group B). Among these 13 patients, 12 were affected with lesions of relevance (in group A, 6 had squamocellular carcinoma and 2 had low-grade dysplasia; in group B, 2 patients had high-grade dysplasia, 2 had low-grade dysplasia, and 1 had an epithelial hypertrophy with inflammatory cells). Preliminary results seem to indicate that autofluorescence is a high-performing test for the individuation of oral cancer in populations at risk (sensibility up to 100% and specificity up to 93% in this study).