HIV-specific T-cell response in HIV-infected individuals at different stages of the disease and during zidovudine therapy was studied using HIV and HIV-envelope derived native and recombinant proteins as antigens. Neither antibody-negative at-risk individuals nor HIV-infected individuals responded to HIV or its envelope-derived proteins, even though they responded to a recall antigen, purified protein derivative of tuberculin (PPD). However, five out of 14 antibody- and antigen-negative sexual partners of known HIV-positive men did respond to HIV, native gp 120 and recombinant envelope and core proteins. Some AIDS-related complex (ARC) and AIDS patients treated with zidovudine also showed a low T-cell response which diminished along with clinical deterioration. A synthetic peptide representing one of the major T-cell epitopes in HIV envelope, frequently recognized by immunized and infected primates, gave only marginal stimulation in man. Our findings suggest that HIV infection in man results in a T-helper cell anergy directed against viral proteins. The response observed in the antibody- and antigen-negative sexual partners and in some of the zidovudine-treated patients implies that at least some epitopes on HIV envelope are immunogenic in man.