Objective To determine whether isotretinoin (or 13-cis-retinoic acid) decreases the risk of second primary cancers in patients previously treated for cure of head and neck squamous cell carcinoma. Design Randomized, double-blind, placebo-controlled trial. Setting Two head and neck multidisciplinary cancer clinics in university teaching hospitals taking cases from 4 to 5 million people in Queensland, Australia, combined to enter appropriate patients into this trial. Patients One hundred fifty-one patients with their first head and neck squamous cell carcinoma treated with high expectation for cure and living close by. They were randomized into 3 arms to receive 3 years of treatment. Interventions Patients took isotretinoin at a high dose (1.0 mg/kg per day) or a moderate dose (0.5 mg/kg per day) or placebo. Group 1 took the high dose for 1 year and then the moderate dose for 2 years. Group 2 took the moderate dose for 3 years. Group 3 took placebo for 3 years. Main Outcome Measures The diagnosis of a second primary malignancy of the head and neck, lung, or bladder was regarded as the end point signifying failure of therapy. Issues of drug adverse effect profile and impact on survival were measured. Results There was no significant difference in the occurrence of second primary disease (P = .90), the recurrence of primary disease (P = .70), or disease-free time (P = .80) between the treatment and nontreatment arms. Numbers were too small to find differences in survival. Conclusion With evidence that retinoid treatment adversely affects survival of lung cancer and with this drug not significantly decreasing the incidence of second primary tumors of head and neck squamous cell carcinoma, the use of this drug in head and neck cancer patients for second cancer prophylaxis is not indicated.