Serologic methods of typing for hepatitis C virus offer advantages over PCR-based typing methods in terms of speed and simplicity of sample preparation and in the use of standard laboratory equipment. We examined the sensitivities and specificities of two hepatitis C virus serotyping assays which use sets of type-specific antigenic peptides derived from the core or the nonstructural 4 (NS4) regions and compared the results with those of molecular typing with type-specific primers from the core region. Although there was a good concordance between serotyping by either assay and genotyping, we found that the sensitivities of both serologic assays were less than optimal compared with that of molecular typing, with only about 50% of samples being unequivocally typed. Moreover, amino acid sequence similarities within the regions of the genome used for serotyping preclude differentiation into subtypes, which may have important clinical and therapeutic implications.