Combination antiretroviral therapy (cART) against HIV infection dramatically reduces AIDS-related morbidity. However, many patients under cART display HIV-associated lipodystrophy. Moreover, some develop early age-related comorbidities. Thymidine analog reverse transcriptase inhibitors (tRNTIs) are mainly responsible for peripheral lipoatrophy, and protease inhibitors (PIs) for fat hypertrophy and metabolic complications. Long-term HIV infection probably also causes fat alterations. Severe mitochondrial toxicity and oxidative stress cause lipoatrophy, whereas the hypertrophy of upper body fat depots could result from mild oxidative stress, cortisol activation and inflammation. The metabolic complications associated with lipodystrophy are responsible for increased cardiovascular and hepatic risks and could also participate in premature aging. We propose that adipose tissue injury by HIV and cART induces fat hypertrophy or atrophy and contributes to premature aging.