Folate-mediated incorporation of [ring-2-14C]histidine into DNA and its modulation under thyroid stress have been studied. Both hyperthyroidism and hypothyroidism decrease the folate-mediated incorporation of the one-carbon unit derived from histidine into DNA significantly, resulting in growth retardation. In concurrence with previous reports, in vivo oxidation of histidine is decreased in hyperthyroidism and increased in hypothyroidism. 5,10-Methylenetetrahydrofolate reductase levels are elevated in hyperthyroidism and decreased in hypothyroidism, whereas methionine synthase levels are decreased in hyperthyroidism and increased in hypothyroidism. It is discussed how in both hyperthyroidism and hypothyroidism folate cofactor-mediated reactions are adversely affected.