Vascular endothelial growth factor (VEGF), a secreted endothelial cell‐specific mitogen, is produced in endocrine organs and regulated by trophic hormones. Because angiogenesis and osteogenesis are closely regulated, we studied whether human osteoblast‐like cells produce VEGF, and if so, what factors regulate VEGF mRNA expression. Human osteoblast‐like cells (HObLC) derived from trabecular bone explants were cultured in α‐MEM supplemented with 10% fetal calf serum. Northern blot analysis revealed that HObLC expressed VEGF mRNA, as did several human osteosarcoma cells. 1,25‐(OH)₂D₃ increased the steady‐state levels of VEGF mRNA in a time‐ and concentration‐dependent manner in HObLC and one of the osteosarcoma cell lines, SaOS‐2, accompanied by an increase in the concentration of immunoreactive VEGF in the conditioned medium. PTH and IGF‐I also increased the level of VEGF mRNA in HObLC and SaOS‐2 cells. Furthermore, 12‐O‐tetradecanoylphorbol ester stimulated VEGF mRNA in a time‐and concentration‐dependent manner. The VEGF mRNA expression induced by 1,25‐(OH)₂D₃ was completely inhibited by H‐7, but only partially by staurosporine. We have demonstrated that PTH, IGF‐I, and most potently 1,25‐(OH)₂D₃ stimulate the mRNA expression and secretion of VEGF in human osteoblast‐like cells, suggesting that one of the anabolic effects of 1,25‐(OH)₂D₃ on skeletal tissue may be mediated by VEGF produced by osteoblasts.