During the last decades, the improvements in the assessment and management of cardiovascular risk have been successful in the reduction of acute cardiovascular outcomes. Among different prevention and therapeutic strategies, treatments targeting HDL increase have been indicated as promising interventions from both basic research and clinical studies. Although this therapeutic approach still requires confirmatory findings from large clinical trials, emerging evidence indicates that it would be particularly useful in some patient categories characterized by accelerated atherosclerotic diseases. In this regard, HIV-infected patients (under antiretroviral treatment or not) have been recently indicated as an appropriate target population. The present review will discuss the promising role of HDL in HIV-related cardiovascular pathophysiology and update novelties from clinical studies targeting HDL increase in HIV patients.