Rationale: The outcome of precancerous bronchial lesions is not well known, and their management is subject to controversy. Many molecular alterations are present in preinvasive lesions, but none has been assessed to predict the evolution of the lesions. Objective: To analyze the outcome of high grade precancerous lesions according to their molecular profile. Methods: 23 severe dysplasia and 31 carcinoma in-situ (CIS) in 37 patients were followed-up using repeated autofluorescence bronchoscopy over a 12 years period. Microdissection and PCR analysis were performed on paraffin tissue sections to assess loss of heterozygosity (LOH) and microsatellite instability on chromosome 3p, 5q, and 9p. Histology and molecular status at baseline were compared between 7 lesions that became invasive, 11 that relapsed after treatment, 17 that were eradicated with local treatment, and 19 that spontaneously regressed. Results: 94% of lesions that progressed or relapsed were CIS at baseline whereas 79% of spontaneously regressing lesions were severe dysplasia (p<0.0001). 3p and 9pLOH were more frequent in CIS than in severe dysplasia (p=0.03). In the whole group of lesions as well as in the CIS group, 3pLOH was strongly associated with progression (p<0.0001 and p=0.02, respectively). Microsatellite instability was not associated with the outcome of the lesions. A therapeutic strategy based on the presence of 3p or 9p LOH, would have led to overtreat 6 lesions but would have missed only one among the 18 progressing lesions. Conclusions: Baseline histology and 3pLOH analysis appear to be useful to predict the outcome of high grade precancerous lesions