Neural tube defects (NTD) are serious congenital abnormalities that have a multifactorial etiology, including both genetic and environmental effectors (for example, diet and/or drugs). Valproic acid (VPA) is a frequently used anti-epileptic drug that has a potentially teratogenic character, as well as the capacity for inducing NTD and other less serious malformations. However, the mechanism of action of VPA has not been clearly established, and it has been suggested that it interferes in the folate cycle and therefore, with the methionine/methylation, possibly through a metabolic blocking of some biomarker that is a key of the cycle, such as for example S-adenosylmethionine (SAM) and folic acid (FA). The objective of the present study is to analyze the morphological and histological changes, which can occur in a high risk experimental model after the administration of VPA as well as for the induction of NTD and other malformations. In addition, the protective roles of the administration of folic acid, 5-formyltetrahydrofolate (FOL) and S-adenosylmethionine (SAM) are assessed. For this pregnant "Wistar" rats classified according to the following treatments: 1) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy); II) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) and FOL (4 mg/kg/day i.p. on days 8, 9, and 10 of the pregnancy); III) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) + SAM (10 mg/kg/day, on days 1-10 of the pregnancy); IV) CONTROL (no treatment). VPA decreases the fertility index by 25% compared to the control group, it increases the number of reabsorptions by mother (1.3 +/- 0.5 vs 1.0 +/- 0.5), and decreases the number of fetuses compared to the control (9.0 +/- 1.4 vs. 12.6 +/- 0.9). In the VPA + FOL group, the numbers for these parameters approach those of the control group and the VPA + SAM group is no different from the VPA group, showing no protective factors. With respect to the bone alterations observed, when these are grouped according to whether they affect the skull, trunk, and extremities, it is seen that there are no significant differences between the groups. The histological study and the immunohistochemical analysis show liver alterations in all groups treated, and a lower number of lymphocytes in the VPA group, and a greater number of Kupffer cells, The results are discussed in relation to, first, the effect of VPA per se in the interference of the methionine/methylation cycle, and secondly, with regard to how folic acid and/or S-adenosylmethionine can improve or not some of the harmful effects induced by VPA.