Abstract Recent studies have suggested including nonstructural proteins as Tat and Vpr in HIV vaccines. However, little is known about the CD4 + T‐cell response that these small proteins induce in humans. We have therefore evaluated these responses by in vitro priming experiments of CD4 + T lymphocytes harvested in healthy donors. In the Tat protein, only one peptide primed CD4 + T cells of eight HLA unrelated healthy donors. T cells induced by this peptide recognized immature DC loaded with the native Tat protein and are restricted by multiple HLA‐DR molecules, in agreement with its binding capacity. This peptide was therefore processed in an appropriate manner and was highly immunoprevalent. CD4 + T‐cell response to Vpr peptides was more disperse and involved six different peptides depending on the HLA‐DR molecules of the donors. Two overlapping peptides were T‐cell stimulating in at least half of the donors. T‐cell response to Vpr in multiple donors is the result of a combination of several CD4 + T‐cell epitopes with good to moderate immunoprevalence. Altogether, our results show that the frequency of responders to HIV Tat or Vpr proteins relies on one or multiple CD4 + T‐cell epitopes, respectively.