Introduction: Both natural history and epidemiological trend of HIV infection have been deeply modified by the introduction of highly active antiretroviral therapy (HAART), around twenty years ago.
Methods: However, despite a rapid drop of the incidence of the large majority of opportunistic infections, a slow, but continued increase of malignancies occurred, with particular evidence focused on cancers which are not strictly related to the definition of full blown AIDS (the so called non-AIDS-defining malignancies).
Results: The unique clinical occurrence of HIV infection complicated by even four non-AIDS-defining cancers prompted us to re-discuss the epidemiology and the possible pathogenesis, the clinical presentation, and the differential diagnosis of this pathologic presentation.
Conclusions: On the ground of our experience in this field, and the available literature evidences, we discuss how this clinical occurrence is acting on HIV infection presentation during the HAART era of the third millennium. These changes need broad scale studies, and promise relevant consequences on etiopathogenetic, prevention, therapeutic, and management aspects of HIV disease in the next future.