The ex vivo response to three HLA-DR-restricted Nef peptides (Nef 66-97, Nef 133-159, Nef 180-202) and one HLA-DQ-restricted Nef peptide (Nef 56-68) was evaluated in 28 HIV-seropositive patients and 6 Long-term Non-Progressors (LTNPs). Analyzing specific proliferative response and IFN-gamma secretion, patients were identified as high responders, medium responders and non-responders to peptides. As high responder patients, LTNP patients showed strong proliferative response to all the Nef-peptides as strong IFN-gamma secretion. Twenty-four months later, all high responder patients were always without antiretroviral treatment whereas 50% of medium responders and at least 66% of low responder patients followed bi-therapy. CDC classification confirmed also unfavourable evolution for these two last groups. All high responder patients conserved stable CD4 counts, proliferative response to Nef peptides as strong IFN-gamma secretion during this 24-month period. So, early good T CD4 response to peptides of the Nef protein could thus be regarded as a factor of good prognosis in HIV infection and a tool of importance in the decision to put or not a patient under treatment.