Little is known about the natural history of precancerous bronchial lesions. Histological changes occurring in 416 bronchial intraepithelial lesions (104 high-risk subjects) were assessed over a 2-yr period, using repeated follow-up autofluorescence endoscopies. During the study, 6 of 36 normal epitheliums became dysplastic; 47 of 152 metaplasia evolved to low-grade dysplasia, two progressed to carcinoma in situ, and one to invasive cancer; 6 of 169 low-grade epithelial lesions progressed to a persistent severe dysplasia; 10 of 27 severe dysplastic lesions and 28 of 32 carcinoma in situ persisted or progressed, respectively (p = 0.0005, severe dysplasia versus carcinoma in situ 24 mo outcome). Carcinoma in situ appeared more frequent in patients with a prior history or concomitant cancer (p = 0.003). Persistence of smoking during the study did not influence high-grade lesion outcome. Progression of low-grade epithelial lesions during the study occurred only in patients with at least a high-grade lesion in another site at baseline (9 of 147 lesions, 6.1%). Our study suggests that low-grade epithelial lesions could be safely followed-up at 2 yr in patients without high-grade lesions at baseline, whereas severe dysplasia should be treated if they persist at 3 mo. Immediate treatment of carcinoma in situ appears warranted.