HIV evades host immune responses through multiple mechanisms including high mutation rate, downregulation of host-cell, HLA class I molecules and depletion of key immune cells. Accordingly, an effective therapeutic vaccine approach to controlling HIV infection will nost likely need to modulate several pathways of both the innate and adaptive immune system. We propose the use of heat shock protein-peptide complexes (HSPPCs) to address this challenge. HSPPCs have been tested for 10 years in cancer patients with signals of clinical activity in phase I and II trials, and the results of two randomised phase III trials are anticipated in the near future. As the cancer setting can also be considered one of chronic disease, the rationale for using HSPPCs to treat HIV infection is clear. Several types of HSPPC vaccines that may be manufactured for testing in HIV-positive patients are discussed, including generation of an autologous vaccine derived from peripheral blood monloonuclear cells (PBMCs) of infected individuals.