Small globular proteins have a compact structure; therefore, their thermal denaturation is described using a two-state model (N⇄D). However, some protein structures exhibited an exception to the two-state mode as implied by the two endothermic peaks in the DSC thermograms, indicating the occurrence of a complicated thermal transition (nN⇄In⇄nD) at high temperatures. The detailed analysis of DSC results indicated that this irregular phenomenon in the thermal denaturation of small globular proteins could be attributed to a reversible oligomerization (RO) at high temperature. RO was significantly destabilized by a single mutation in the hydrophobic amino acid at the interface of the crystallographic oligomer in the native state. The destabilization of the RO of PSD95-PDZ3 resulted in the inhibition of the amyloid fibrils generated by the incubation at 60℃ for 1 week. Therefore, RO was hypothesized as the precursor of protein thermal aggregation, and this observation would enable us artificially control the thermal aggregation tendency of proteins.