Antiretroviral therapy (ART) has significantly reduced the morbidity and mortality of patients infected with the human immunodeficiency virus 1 (HIV-1). In a significant number of patients, ART is associated with fat redistribution and metabolic alterations such as dyslipidemia, insulin resistance (IR) and type 2 diabetes, summarized under the term HIV-associated lipodystrophy syndrome (HIV-LS). The pathogenesis of HIV-LS is complex and involves a number of factors including ART, HIV-1, abnormal fat redistribution, metabolic abnormalities and chronic inflammation. In view of a novel understanding on how chronic inflammation contributes to the pathogenesis of HIV-1 infection, this review focuses on the interaction of the immune system and metabolic pathways and the potential consequences for the HIV-LS. Based on the current literature, we suggest a central role of systemic inflammation in triggering and deteriorating various components of the HIV-LS.