To detect positive selection in protein-coding sequence evolution, the ratio of the nonsynonymous to synonymous substitution rate (K(A)/K(S)) is commonly used. When this ratio is higher than 1, positive selection on nonsynonymous changes is considered to have occurred. However, the question of what kinds of amino acid change are likely to be involved in positive selection has not been well studied, though intuitively it seems that radical changes frequently occur in positively selected changes. To address this question, we examined chemically radical and conservative replacements in the evolution of hepatitis C virus (HCV) protein sequences. In the envelope region, 34 positively and 440 negatively selected sites were identified by the K(A)/K(S) ratio. Radical and conservative changes were compared between the two types of selected sites using two methods. First, the numbers of radical and conservative replacements were counted at the positively and negatively selected sites according to three kinds of chemical classifications. In all three classifications, the resulting ratios of the two numbers were not statistically different for the two types of selected sites (P>0.05). Second, the distribution of chemical changes was compared between the two types of selected sites using two kinds of chemical distances. The distributions of the two chemical distances were not statistically different for the two types of selected sites (P>0.05). These results indicate that the ratio of chemically radical and conservative changes is similar for positively and negatively selected sites in the envelope protein of HCV or, in other words, there is no correlation between radical change and positive selection in the evolution of this protein.