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A primary function of the hepatitis C virus (HCV) core protein is to package the viral genome within a nucleocapsid. In addition, core protein has been shown to interact with more than a dozen cellular proteins, and these interactions have been suggested to play critical roles in HCV pathogenesis. A more complete knowledge of the biophysical properties of the core protein may help to clarify its role in HCV pathogenesis and nucleocapsid assembly and provide a basis for the development of novel anti-HCV therapies. Here we report that recombinant mature core protein exists as a large multimer in solution under physiological conditions. Far-UV circular dichroism (CD) experiments showed that the mature core protein contains stable secondary structure. Studies with truncated core protein demonstrated that the C-terminal region of the core protein is critical for its folding and oligomerization. Intrinsic fluorescence spectroscopy and near-UV CD analysis indicated that the tryptophan-rich region (residues 76–113) is largely solvent-exposed and not likely responsible for multimerization of the mature core protein in vitro. [Copyright &y& Elsevier]