Background Technology that highlights potentially malignant oral lesions in a highly sensitive and specific manner will aid clinicians in early diagnosis of these conditions. This study assessed the efficacy of direct tissue autofluorescence imaging Visually Enhanced Lesion Scope (VELScope) in the detection of oral mucosal lesions. Methods One hundred twelve patients referred with a potentially malignant oral mucosal lesion were examined under routine incandescent light, and then with VELScope, noting loss of autofluorescence and presence of blanching. Incisional biopsies were performed to provide definitive histopathological diagnoses. Results VELScope enhanced the visibility of 41 lesions and helped uncover 5 clinically undetected lesions. VELScope examination alone showed a sensitivity of 30% and a specificity of 63%. Its accuracy at identifying dysplasia was 55%. Conclusion VELScope examination cannot provide a definitive diagnosis regarding the presence of epithelial dysplasia. Loss of autofluorescence is not useful in diagnosing epithelial dysplasia in its own right without relevant clinical interpretation.