N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid with anticarcinogenic activity, has been shown to lower the plasma retinol level rapidly and significantly. We reported previously that vitamin A-deficient rats (plasma retinol < 0.175 mumol/l) have a low number of natural killer (NK) cells in peripheral blood. To investigate the effects of 4-HPR on NK cell number and activity, two studies were conducted. In study 1, vitamin-A-sufficient rats were fed a 'therapeutic' dose of 4-HPR (2 mmol/kg of diet) for 30 days. Despite a low plasma retinol concentration (approximately 0.1 mumol/l), the number of NK cells was not reduced. Moreover, the NK cytolytic activity per cell was significantly elevated. White blood cell and differential counts were normal. In study 2, the biological activity of 4-HPR was examined in vitamin-A-deficient rats. Rats depleted of vitamin A were fed a diet containing 4-HPR (54.7 micrograms/g of diet) for 11 days. Vitamin-A-dependent processes including growth, hematocrit, lymphocyte count and the number of NK cells were restored. For comparison, another group of vitamin-A-deficient rats were repleted with retinoic acid (RA; 4.2 micrograms/g diet); this treatment also effectively restored these vitamin-A-dependent processes. Therefore, despite the plasma-retinol-lowering property of 4-HPR, treatment with this retinoid did not impair NK cell number or function. Indeed, 4-HPR showed vitamin A activity similar to RA, and may stimulate NK cell cytotoxicity.