To investigate whether highly active antiretroviral therapy (HAART) could improve CD28 molecule expression and CD28-costimulation pathway function we tested the effect of CD28-costimulation on T cell receptor/CD3 induced proliferative responses in a group of HIV-1-infected subjects with CD4+ cells>200/mmc before and after HAART. CD3-mediated responses are recovered or improved after HAART. However the ability of potentiating the responses through CD28-costimulation seemed conserved before therapy and decreased in parallel with increase of response to CD3 alone. These results confirm the integrity of CD28-pathway of costimulation in patients with CD4+ cells>200/mmc and suggest an inverse correlation between magnitude of response to CD3 alone and increase of CD3 response due to anti-CD28 addition.