The success of highly active antiretroviral therapy (HAART) in reducing AIDS-related mortality means that in regions where HAART is available, HIV infection may now be regarded as a chronic disease. However the inability of HAART to eliminate HIV-1 from various anatomical and cellular reservoirs within the body means that HIV-infected individuals require life-long treatment with therapy that can have significant side effects. Management of HIV disease is therefore increasingly focused on drug-related toxicities and the improvement of current HAART regimens. Here we review the potential use of immunomodulatory cytokines to directly or indirectly stimulate the mononuclear phagocyte system as adjuncts to current HIV treatment as well as their use in the management of opportunistic infections in individuals who develop immunodeficiency. We argue that cytokines, which stimulate mononuclear phagocyte activity against opportunistic pathogens, may be useful for the treatment of individuals who develop recurrent opportunistic infections. Cytokines may act synergistically with antimicrobial agents to improve outcomes, which is of particular importance since recurrent infections frequently result in resistance to standard antimicrobial treatments. Before their use can be advocated however, given their toxicity and significant cost, the potential benefits of cytokines must be demonstrated in larger clinical trials.