Previously, we hypothesized that mycoplasmas could act as cofactors accelerating the progression of HIV disease. In the present paper, we review the current knowledge on three mycoplasmas (Mycoplasma fermentans, M. penetrans, and M. pirum) that have been implicated as these putative cofactors. All three mycoplasmas have been isolated from patients with HIV infection, and serological studies have suggested that the presence of M. penetrans could be associated with HIV infection. These mycoplasmas share the capacity to hydrolyze arginine and ferment glucose as well as to attach to and invade eukaryotic cells. The possible mechanisms that could allow mycoplasmas to influence HIV pathogenesis, specifically through the activation of the immune system or the production of superantigen or by contributing to the oxidative stress observed in HIV-infected subjects, are discussed. These studies have offered and will continue to offer major contributions to a better understanding of mycoplasmal flora in humans and have begun to unveil some of the mechanisms of virulence of these organisms.