Endobronchial carcinoma develops through a continuum of morphologically recognizable pre-neoplastic changes. At present, no marker has been identified that can reliably predict the biological behavior of these lesions. Endobronchial lesions (n=39) sampled from patients (n=20) without clinically overt lung cancer, were analyzed by immunohistochemistry (IHC) for abnormal expression regarding the p53 protein, i.e. suprabasal p53 expression. Clear suprabasal p53 immunostaining was found in two (12%) of the hyperplastic or squamous metaplastic lesions, in one (10%) of the mildly or moderately dysplastic lesions and in nine (75%) of the severely dysplastic or carcinoma in situ (CIS) lesions. Suprabasal p53 immunostaining was found significantly more frequent in severe dysplasia or CIS (P<0.01). Of 17 patients follow-up data were available. After a median follow up of 7 months (range 2-37 months), six patients presented with bronchial carcinoma within the same lobe or bronchial spur where biopsies had been taken. Four of these patients revealed suprabasal p53 immunostaining in the biopsies obtained from the sites of future cancer. In three patients biopsies were obtained from future cancer sites as well as from distant sites in the ipsilateral lung. Suprabasal p53 immunostaining was found exclusively at future cancer sites of these patients (P=0.02). Suprabasal p53 immunostaining in addition to histology improved the specificity and the positive predictive value for bronchial carcinoma development in the same lobe or bronchial spur, compared with histology alone. These results suggest that suprabasal p53 immunostaining is associated with bronchial cancer and might have additive value to predict the biological behavior of pre-neoplastic endobronchial lesions in the population at risk of bronchial cancer.