An in vitro model of trophoblast cell differentiation has been used to examine the developmental expression of retinoid receptor mRNAs during the differentiation of human placental cytotrophoblast cells to syncytiotrophoblast cells. The levels of RAR alpha, RAR beta, RXR alpha mRNA increased by 12, 7, and 3 fold, respectively, during trophoblast differentiation, while the levels of RAR gamma mRNA remained relatively constant; and the increase in retinoid receptor mRNA expression preceded the increase in the expression of placental lactogen (hPL), a specific marker of syncytiotrophoblast cells. CRABP-II mRNA levels were lower in cytotrophoblast cells than in syncytiotrophoblast cells. Mobility shift assays demonstrated the appearance of a specific band that bound to a labeled DNA probe containing a retinoic acid responsive element (RARE) that was most intense from nuclear extracts from syncytiotrophoblast cells. These results suggest possible roles for these receptors in the regulation of trophoblast differentiation and hPL gene expression.