We reacted 490 hexapeptides homologous to the amino acid sequence of the dengue 2 (DEN-2) virus envelope glycoprotein with antisera from 7 patients with primary DEN-2 virus infections to identify the continuous epitopes recognized by human IgG. There were 124 peptides in 25 clusters (domains) that bound 2 or more antisera. Twenty-two peptides in 7 domains bound all 7 convalescent DEN-2 virus antisera tested, and thus appeared to represent immunodominant epitopes. The evidence that these domains represent continuous epitopes of the envelope glycoprotein is that peptides representing each domain bound multiple sera, peptide reactivity was highly ordered along the amino acid sequence, and in almost all cases, domains were regions of predicted hydrophilicity. Heterologous flavivirus antisera also exhibited binding to the majority of peptides reactive with anti-DEN-2 virus sera, though 4 candidate DEN-2 specific epitopes were identified along with an immunodominant epitope common to dengue, Japanese encephalitis and West Nile viruses. Synthetic peptides representing these epitopes may prove to be useful for a variety of purposes.