Peptides bound by human class I major histocompatibility complex molecules and presented to cytotoxic T cells (CTL) were predicted by a computer algorithm, and changes in these predicted CTL epitopes (pCTLE) were reconstructed by maximum parsimony in a phylogeny of complete genotypes of dengue virus, West Nile virus (WNV), and Japanese encephalitis virus (JEV). In a clade including dengue virus serotypes 1 and 3 (D1V and D3V), pCTLE were lost over evolutionary time at a greater rate than new ones were gained. A similar but less pronounced trend was seen in the other dengue serotypes but not in WNV and JEV. The loss of pCTLE predicted to be restricted by HLA-B(*)2705 was particularly pronounced in D1V and D3V. Since dengue is endemic in humans, while WNV and JEV are not, these results are consistent with CTL-driven selection on dengue viruses, particularly, D1V and D3V.