Patients receiving long-term antiretroviral therapy are at increased risk of age-associated non-AIDS-related morbidity and mortality compared with HIV-seronegative persons. Despite suppressive antiretroviral treatment, inflammation remains elevated and CD4+ count often remains low, with both measures predicting age-associated events. Several factors likely contribute to persistent inflammation and suboptimal gains during therapy. These include residual HIV replication, persistent virus expression, loss of immunoregulatory cells, collagen deposition, microbial translocation, chronic coinfections, and thymic dysfunction. How these factors influence disease outcomes and how chronic inflammation should be managed during therapy are the focus of intense ongoing investigation. Currently, the most practical advice is to start antiretroviral therapy early and to manage traditional risk factors for non-AIDS-related conditions aggressively. This article summarizes a presentation made by Steven G. Deeks, MD, at the International AIDS Society-USA continuing medical education program in Chicago in May 2009.