We evaluated the role of dietary phytoestrogens (PE) in the disease phenotype of cold intolerance that characterizes long-chain acyl-CoA dehydrogenase-deficient (LCAD-/-) mice, a model of inborn errors of mitochondrial fatty acid beta-oxidation. Male LCAD-/- mice were fed a standard diet containing endogenous PE, a PE-free diet, or a PE-free diet that was supplemented with genistein (250 microg/g diet). The standard diet did not restore complete cold tolerance, but it provided more resistance (P = 0.004) to cold challenge than the PE-free diet. There was a nonsignificant difference (P < 0.07) between LCAD-/- mice fed the genistein-supplemented diet and those fed the PE-free diet. There were no differences in end-point serum glucose concentrations among the 3 groups. Serum FFA were decreased in LCAD-/- mice fed the standard diet compared with those fed the PE-free diet (P = 0.005) and the diet supplemented with genistein (P < 0.001). Serum triglyceride concentrations were greater (P < 0.05) only in LCAD-/- mice fed the genistein-supplemented diet than those fed the standard diet. These results demonstrate the beneficial effects of dietary PE on metabolic tolerance in LCAD-/- mice. Furthermore, they suggest changes that could improve pediatric formula constituents, especially with regard to management of children with inborn errors of fatty acid oxidation.