The thermal stability of horse spleen apoferritin, a heteropolymer composed of 90% L and 10% H chains, has been studied by differential scanning calorimetry and compared with that of the human recombinant H homopolymer. The denaturation temperatures (Tm) are significantly higher for the horse spleen polymer than for the recombinant protein under all experimental conditions (e.g., at pH 7, Tm values are > or = 93 and 77 degrees C, respectively). The thermal denaturation process displays substantial reversibility for both polymers up to a few degrees below Tm, as indicated by CD measurements in the far and near uv regions. At temperatures higher than Tm the thermograms are influenced by the exothermic contribution of aggregation and/or precipitation. The H homopolymer thermogram, which is not distorted by the exotherm, is consistent with a multistate denaturation process. Acid dissociation of apoferritin produces stable dimeric subunits. The thermal unfolding of both dimeric subunits is reversible at least up to Tm and is characterized by an inversion of stability relative to the polymers (at pH 3.5, Tm is 42 degrees C for the horse spleen and 50 degrees C for the H subunit). These results indicate that the stabilization of the polymeric structure arises mainly from interactions between dimers, in accordance with the crystallographic evidence that the dimers are the building blocks of the polymeric molecule.