text: PURPOSE: Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS: The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS: After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION: Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored.