Chemoprevention involves efforts to block or reverse carcinogenesis before the development of invasive cancer. Natural agents, such as retinol and beta carotene, as well as synthetic retinoids have been studied as potential chemopreventive agents. In the head and neck, chemoprevention studies have included efforts both to reverse premalignant lesions such as oral leukoplakia and to prevent the development of second primary tumors. In one recent trial, high-dose 13-cis-retinoic acid treatment resulted in a dramatic reduction in the incidence of second primary tumors. However, significant toxicities were associated with the high dosage. This trial, as well as previous studies of oral leukoplakia, have led to the development of a chemoprevention trial using a low dose of 13-cis-retinoic acid to prevent second primary tumors following head and neck cancer. The rationale and design of this study are discussed in detail.