Among HIV-1 proteins, Tat is a promising antigen for consideration as a component of anti-HIV-1 vaccine formulations. Nevertheless, this viral protein is able to affect the expression of several cellular genes that are implicated in immune response. In this study, we designed and characterized a mutant form of Tat ("STLA Tat"), which is unable to transactivate viral transcription, and which has lost the deleterious effects on the expression of MHC I, IL-2, and CD25 genes compared with wild-type Tat, as observed in lymphoid Jurkat cells that stably express the tat genes. In vivo experiments in mice revealed that STLA Tat induces anti-Tat antibodies at the same titers as wild-type Tat, which recognize both autologous and heterologous Tat antigens. Finally, STLA Tat did not induce the immunosuppression observed after injection of wild-type Tat. Therefore, this STLA Tat mutant appears to be a safe and promising antigen for further evaluation in anti-HIV-1 vaccine strategies.