We report that NSBP1, a nucleosome binding protein that affects the structure of chromatin, is highly expressed in mouse placenta. In Rcho-1 cells, which recapitulate the differentiation of trophoblast giant cells of living placenta, NSBP1 expression is linked to differentiation. Disregulation of NSBP1 protein levels, by either siRNA treatment or by overexpression, alters the expression of several members of the prolactin gene family without affecting the levels of several transcription factors involved in placental differentiation. Our studies identify NSBP1 as a nucleosome binding protein that modulates the expression of prolactin gene family members most likely by inducing changes in chromatin structure.