Virus-like particle (VLP)-based vaccines have provided highly encouraging results in clinical trials while, in contrast, DNA vaccines expressing non-particulate proteins have proven less successful. Seeking to combine the immunogenicity of VLPs and the ease of production of plasmid DNA, we designed DNA vaccines expressing VLPs consisting of the MLV Gag and modified MLV Env proteins displaying T cell epitopes. We show here that such DNA vaccines are remarkably efficient immunogens for inducing cellular immune responses. In contrast to similar plasmids harboring a point mutation preventing VLP formation, they induce protection against a lethal viral challenge in mice. Thus, these "plasmo-retroVLPs" represent a promising second-generation DNA vaccine.