We have studied the effect of 1,25-dihydroxyvitamin D3 (1,25, (OH)2D3) on mesangial cell growth. Previous studies have shown that the monocyte-macrophage is the principal effector cell in immune-mediated nephritis; this cell infiltrates the glomerular mesangium, and its products may have important effects on the physiology of the mesangial cell. One of the substances produced by the activated macrophage is 1,25,(OH)2D3. We have investigated the effect of 1,25,(OH)2D3 on mesangial cell growth and found that this vitamin D metabolite suppresses the proliferation of mouse mesangial cells as assessed by mesangial cell tritiated thymidine uptake and by cell counts; this substance also antagonizes the mitogenic effect of epidermal growth factor on mesangial cell growth. By comparison, the vitamin D metabolite 25 hydroxyvitamin D3 has no significant suppressive effect on the proliferation of mesangial cells. It has also been possible to demonstrate that 1,25,(OH)2D3 could suppress the growth of mesangial cells that had been committed to proliferate by the prior addition of epidermal growth factor. The results of these studies are relevant to our understanding of the pathogenesis of the cellular abnormalities that occur in immune-mediated nephritis, and especially in subjects who have concurrent hypertension, because a segment of subjects with hypertension have demonstrable abnormalities in the levels of circulating 1,25,(OH)2D3.