The conformation of porcine serum ferric transferrin (Tf) and its stability against denaturation were studied by circular dichroism. Tf was estimated to have 19-24'70 a-helix and 50-55'70 fl-sheet based on the methods of Chang et al.(Chang, CT, Wu, C.-SC, & Yang, JT, 1978, Anal. Biochem. 91, 13-31) and Provencher and Glockner (Provencher, SW & Glockner, J., 1981, Biochemistry 20, 33-37). Removal of the bound ferric ions (apo-Tf) did not alter the overall conformation, but there were subtle changes in local conformation based on its near-UV CD spectrum. The Tfs were stable between pH 3.5 and 11. Denaturation by guanidine hydrochloride (Gu-HCI) showed two transitions at 1.6 and 3.4 M denaturant. The process of denaturation by acid and base was reversible, whereas that by Gu-HCI was partially reversible. The irreversible thermal unfolding of Tfs began at temperatures above 60" C and was not complete even at 80" C. The bound irons (based on absorbance at 460 nm) were completely released at pH< 4 or in Gu-HCI solution above 1.7 M, when the protein began to unfold, but they remained intact in neutral solution even at 85" C. The NH2-and COOH-terminal halves of the Tf molecule obtained by limited trypsin digestion had CD spectra similar to the spectrum of native Tf, and the COOH-terminal fragment had more stable secondary structure than the NH,-terminal fragment.