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The current status of HIV infection and treatment.HIV protease inhibitors (PIs) induce side effects in GI tract via ER stress.HIV PIs induce inflammatory response via activation of ER stress.HIV PIs-induced ER stress and dysfunction of GI contribute to hepatic injury.The development of HIV protease inhibitors (HIV PIs) has been one of the most significant advances of the past two decades in controlling HIV infection. HIV PIs have been used successfully in highly active anti-retroviral therapy (HAART) for HIV infection, which is currently the most effective treatment available. Incorporation of HIV PIs in HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality of HIV infection, and prolongs the lifespan of HIV patients. However, in the era of HAART, drug-induced gastrointestinal (GI) side effects and hepatotoxicity have emerged as important potential complications of HIV therapy, particularly those regimens containing HIV PIs. In this mini-review, we highlight the current understanding of the mechanisms of HIV PI-associated GI and liver injury.