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1,25-dihydroxyvitamin D3(1,25-(OH)2D3), a metabolically active form of vitamin D, is shown to increase in a dose-dependent manner the cellular pool of NGF mRNA in murine L-929 fibroblasts cultured in a serum-free medium. This effect can be detected as early as 3 hours after 1,25-(OH)2D3 addition and persists for at least 28 hours. It is accompanied by an enhancement of the amount of NGF-protein secreted in the culture medium. Since the proto-oncogene c-fos appears involved in the regulation of the NGF gene (Mocchetti et al.: Proceedings of the National Academy of Sciences of the United States of America 86:3871-895, 1989; Hengerer et at: Proceedings of the National Academy of Sciences of the United States of America87:3899-3903, 1990), the effect of 1,25-(OH)2D3on c-fos expression was analysed and compared to that elicited by other inducers of the NGF gene, serum (Wion et al: FEBS- Letters 189:37-41, 1985) and phorbol 12-myristate 13-acetate (PMA) (Wion et al: FEBS Letters 262:42-44, 1990). Addition of serum or PMA to L-929 cells was; rapidly followed by a transient activation of the c-fos gene. In contrast,c-fos transcripts remained undetected in the presence of 1,25-(OH)3D3 The failure to find any evidence of c-fos expression suggests that 1,25-(OH)2D3could enhance the pool of NGF mRNA by a mechanism independent of the c-fos pathway. The effective concentration range, as low as 10−10 M raises the possibility that 1,25-(OH)2D3 could represent one of the serum factors that might contribute to the regulation of the NGF gene in vitro and possibly in vivo. This suggests a possible therapeutic interest for 1,25-(OH)2D3in neurodegenerative diseases.