Rationale: Bronchial epithelium exposed to cigarette smoke undergoes a series of histological changes that may ultimately lead to invasive cancer. Inhaled corticosteroids reduce the number of lung tumors developing in rats exposed to cigarette smoke. Objectives: We studied the effect of inhaled fluticasone on premalignant lesions in smokers and patients curatively treated for head and neck cancer or lung cancer. Methods: Participants were screened for premalignant lesions by bronchoscopy. Biopsies were taken from three to five locations and classified using WHO criteria. In case of a metaplasia index of >15%, participants were randomized to receive a powder inhalation device containing either fluticasone 500 µg or a placebo, to be used twice a day. After 6 months, biopsies were obtained from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary end-points were reversal of increased p53 and KI-67 immunoreactivity and hTERT expression. Measurements: Of the 201 subjects that were screened, 108 were included. Mean age was 53 years (35-71), mean number of pack-years 48 (18-99), mean metaplasia index 48% and 32% had some degree of dysplasia at baseline. Main Results: The two treatment arms did not differ with respect to response or change in either metaplasia index or the expression of the markers p53, KI-67 or hTERT. Conclusion: Inhaled fluticasone in a dose of 2x500 µg does not affect the natural course of premalignant lesions in the central airways. www.clinicaltrials.gov NCT 00407264