The purpose of this work was to test the hypothesis that reduced responsiveness of target organs to 1,25‐dihydroxyvitamin D3 [1,25‐(OH)2D3] is associated with osteoporosis. Peripheral blood mononuclear (PBM) cells have been previously shown to be a valid model for the action of 1,25‐(OH)2D3 on its classic target organs in various pathologic and physiologic situations. The responsiveness of lymphocytes to the hormone can be assessed by the extent of inhibition it exerts on the proliferative response to mitogenic lectins. A group of 39 postmenopausal women, at least 10 years after the menopause, participated in the study. Osteoporosis, defined as the presence of at least one nontraumatic vertebral crush fracture, was diagnosed in 19 subjects. Mitogenesis of PBM cells stimulated by phytohemagglutinin and cultured for 72 h in the presence or absence of 1,25‐(OH)2D3 (0.03–1 nmol/liter) was assessed by [3H]thymidine incorporation during a 4 h pulse. The maximal inhibitory effect of 1,25‐(OH)2D3 at saturating concentration (1 nM/liter) was 74.6 ± 2.8% (mean ± SEM) for normal compared to 65.3 ± 2.9% for osteoporotic women (P = 0.015). The geometric mean of the ED50 values of 1,25‐(OH)2D3 was 60% higher in the osteoporotic than in the normal group (P = 0.035). Our data are consistent with the notion that reduced responsiveness of target organs to 1,25‐(OH)2D3 is associated with osteoporosis.