1, 25-Dihydroxyvitamin D 3 (1, 25 (OH) 2 D 3) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1, 25 (OH) 2 D 3 levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1, 25 (OH) 2 D 3 on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1, 25 (OH) 2 D 3, although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1α-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1, 25 (OH) 2 D 3 and/or activation. Importantly, 1, 25 (OH) 2 D 3 up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1, 25 (OH) 2 D 3 may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.