Much effort has been devoted to the analysis of antibodies to acquired immunodeficiency syndrome virus antigens, but no studies, to our knowledge, have defined antigenic sites of this virus that elicit T-cell immunity, even though such immunity is important in protection against many other viruses. T cells tend to recognize only a limited number of discrete sites on a protein antigen. Analysis of immunodominant helper T-cell sites has suggested that such sites tend to form amphipathic helices. An algorithm based on this model was used to identify two candidate T-cell sites, env T1 and env T2, in the envelope protein of human T-lymphotropic virus type IIIB that were conserved in other human immunodeficiency virus isolates. Corresponding peptides were synthesized and studied in genetically defined inbred and F1 mice for induction of lymph node proliferation. After immunization with a 426-residue recombinant envelope protein fragment, significant responses to native gp 120, as well as to each peptide, were observed in both F1 combinations studied. Conversely, immunization with env T1 peptide induced T-cell immunity to the native gp 120 envelope protein. The genetics of the response to env T1 peptide were further examined and revealed a significant response in three of four independent major histocompatibility haplotypes tested, an indication of high frequency responsiveness in the population. Identification of helper T-cell sites should facilitate development of a highly immunogenic, carrier-free vaccine that induces T-cell and B-cell immunity. The ability to elicit T-cell immunity to the native viral protein by immunization with a 16-residue peptide suggests that such sites represent potentially important components of an effective vaccine for acquired immunodeficiency syndrome.