Several immunodominant B-cell epitopes have been mapped in the structural (gag, env) and regulatory (tax, rex) proteins of human T-lymphotropic virus type I (HTLV-I) and HTLV-II. Identification of these immunogenic epitopes not only has allowed the development of sensitive and specific serologic assays, but also has provided a tool to study correlates of host pathogenesis, viral transmission, and protection. The major immunogenic epitopes for HTLV-I are located at the C terminus of p19gag, the central and carboxyl terminus of gp46env, the central region of transmembrane envelope glycoprotein (p21e), and the carboxyl terminus of p40tax. Similarly, HTLV-II epitopes are located at the amino terminus and central region of gp46env, the central region of p21e, and the carboxyl terminus of p40tax. The transmembrane epitopes of HTLV-I and HTLV-II share extensive homologies and represent a highly cross-reactive region, while the remaining regions represent HTLV type-specific epitopes. The transmembrane epitope has been commonly used for detecting antibodies in both HTLV-I and HTLV-II-infected persons, whereas central envelope epitopes have been exploited for serologic differentiation between HTLV-I and HTLV-II. This detailed analysis at the epitope level has resulted in the development of highly sensitive and specific screening and confirmation assays for detection of antibodies to HTLVs.