The neural cell adhesion molecule, NCAM, not only plays an important role in neuronal migration, differentiation and formation of connections in the developing nervous system, but also in the condensation of the mesodermal mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule for preventive strategies aimed at minimizing the effects of teratogens affecting the prenatal development of the nervous system and the skeleton. Treatment of fetuses with the teratogen pyrimethamine results in a reduced body weight, microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia, brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3, partly prevented the defects induced by this treatment. Although intra-amniotic administration of C3 at gestational day 14 had no effect on the pyrimethamine-induced reduction in body weight, it rescued the deficit in brain weight (microcephaly), partly reversed a decrease in thickness of the cortical plate, and significantly reduced the number of malformed fetuses. In vitro, C3 promoted survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in neuroprotection in vivo and in vitro.