Human immunodeficiency virus (HIV) is likely to play a role in the onset of plasma cell tumors (PCT). In fact, HIV could be involved in plasmacytomagenesis in several ways: it has the ability to lessen the immunosurveillance to such a degree as to impair the immune response against tumor cell growth. This decreased immunosurveillance could further facilitate the transforming malignant role of possible Epstein-Barr virus (EBV) infection occurring in this setting. Lastly, a murine retrovirus has been shown to be able to accelerate plasmacytomagenesis in mice, thus indicating that these viruses may be directly involved in the onset of PCT. According to cases previously reported in the literature, the clinical features of this case of HIV-associated PCT were more aggressive and the survival was shorter than expected for PCT cases in the general population. Further, the pattern of alteration of gammaglobulinemia differed in this setting. These alterations strongly suggest a direct role of HIV in PCT. Further in-depth investigations are therefore warranted to elucidate this issue.