ABSTRACT We have recently demonstrated that the myelinolytic lesions in the spinal cord (SC) of rats made deficient in vitamin B 12 (cobalamin) (Cbl) through total gastrectomy (TG) are tumor necrosis factor‐α (TNF‐α)‐mediated. We investigate whether or not permanent Cbl deficiency, induced in the rat either through TG or by chronic feeding of a Cbl‐deficient diet, might modify the levels of three physiological neurotrophic factors—epidermal growth factor (EGF), vasoactive intestinal peptide (VIP), and somatostatin (SS)—in the cerebrospinal fluid (CSF) of these rats. We also investigated the ability of the central nervous system (CNS) in these Cbl‐deficient rats to synthesize EGF mRNA and of the SC to take up labeled Cbl in vivo . Cbl‐deficient rats, however the vitamin deficiency is induced, show a selective decrease in EGF CSF levels and an absence of EGF mRNA in neurons and glia in various CNS areas. In contrast, radiolabeled Cbl is almost exclusively taken up by the SC white matter, but to a much higher degree in totally gastrectomized (TGX) rats. Chronic administration of Cbl to TGX rats restores to normal both the EGF CSF level and EGF mRNA expression in the various CNS areas examined. This in vivo study presents the first evidence that the neurotrophic action of Cbl in the CNS of TGX rats is mediated by stimulation of the EGF synthesis in the CNS itself. It thus appears that Cbl inversely regulates the expression of EGF and TNF‐α genes in the CNS of TGX rats.—Scalabrino, G., Nicolini, G., Buccellato, F. R., Peracchi, M., Tredici, G., Manfridi, A., Pravettoni, G. Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B 12 (cobalamin) in the rat central nervous system. FASEB J . 13, 2083–2090 (1999)