As demonstrated in several in vitro and in vivo cancer models, retinoids have chemopreventive activity. The present studies were performed to evaluate the efficacy of 9-cis-retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl) retinamide (4-HPR), alone and combined, in preventing mammary cancers. Female Sprague-Dawley rats received N-methyl-N-nitrosourea (MNU), 50 mg/kg BW, either at 50 days of age (experiment I, young rats) or at 100 days of age (experiment II, older rats). In experiment I, 9-cis-RA (60 mg/kg of diet), 4-HPR (586 mg/kg of diet), or the combination were evaluated; in experiment II, 9-cis-RA (30 mg/kg of diet), 4-HPR (196 mg/kg of diet), or the combination were tested. There were no signs of toxicity in either study. In the young rats, there were only slight reductions (15-20%) in the number of mammary cancers when the agents were given alone. In the older rats, lower doses of 9-cis-RA or 4-HPR alone were highly effective; with 61% and 46% reductions in the number of mammary cancers, respectively. The combination of retinoids in the young rats caused a 49% reduction in mammary cancers, while in the older rats the combination resulted in a 96% reduction. Thus, lower doses of the retinoids caused more striking inhibition of mammary cancers in older rats than the higher doses given to younger animals. In both experiments, the two retinoids in combination produced an additive effect, suggesting that they may inhibit mammary cancers by different mechanisms.