The active metabolite of vitamin D, 1,25‐dihyd‐roxyvitamin D₃ (1,25(OH)₂D₃), has been shown to enhance the growth of human granulocyte/macrophage haemopoietic progenitors in vitro and to induce these cells to differentiate along the monocyte/macrophage pathway. In order to evaluate the relationship between specific receptors for 1,25(OH)₂D₃ and the role of 1,25(OH)₂D₃ in the regulation of haemopoietic cell differentiation, we examined the effect of 1,25(OH)₂Di on the in vitro growth and differentiation patterns of marrow myeloid progenitor cells from two patients with 1,25(OH)₂D₃ resistant rickets, resulting from defective receptors to vitamin D. A significant rise in the frequency of myeloid colonies in control marrow cell cultures was induced by 2×10⁻⁹ to 2×10⁻⁷ M 1,25(OH)₂D₃. This rise reached a plateau at 2×10⁻⁹–2×10⁻⁸ M 1,25(OH)₂D₃, resulting in a maximal 54±9% increase in colony numbers. In contrast, no stimulatory effect could be detected when 1,25(OH)₂D₃ was added to cultured marrow cells from the patients with 1,25(OH)₂D₅ resistance. Analysis of colony composition revealed that 2×10⁻⁸ and 2×10⁻⁷ M, 1,25(OH)₂D₃ induced a 50±26% increase in the frequency of colonies composed only of monocytes/macrophages in control, but not in the patients’marrow cell cultures. The effect of 2×10⁻⁸ and 2×10⁻⁷ M 1,25(OH)₂D₃ on progenitor cell differentiation towards monocytes/macrophages was also observed in marrow cell suspension cultures. Whereas 1,25(OH)₂D₃ induced a 81–136% increase in the frequency of monocytes in control marrow cells, no effect could be detected on the generation of mature monocytes in marrow cells of the 1,25(OH)₂D₃ resistant patients. Our results show that marrow granulocyte/macrophage progenitor cells from patients with 1,25(OH)₂D₃ resistance fail to respond to 1,25(OH)₂D₃. We thus demonstrate that the effect of 1,25(OH)₂D₃ on the proliferation and differentiation of haemopoietic progenitor cells is mediated through its binding to specific cytoplasmic receptors.