Simple SummaryDid you know that HIV may directly cause organ damage despite the effects of highly active antiretroviral therapy (HAART)? Due to the potency of current HAART, this may look questionable; however, excessive alcohol use may increase the risk of HIV-induced organ damage. While the most implicated organ in the gastrointestinal system is the liver, the pancreas may also be affected. In this study, we aimed to disclose the mechanisms of pancreatitis in alcohol-abusing HIV patients, which is crucial for developing an effective therapeutic strategy. From the literature, we found that alcohol-induced intracellular zymogen activation was mediated by calcium and lysosome hydrolases leading to acinar necrosis. Similarly, HIV entry into pancreatic acinar cells mediates ER and oxidative stress, which triggers acinar necrosis. Infiltration of immune cells has also been reported to induce necrosis. Therefore, effective therapeutic regimens for HIV and alcohol-induced pancreatitis should inhibit HIV entry and ameliorate alcohol’s toxic effects on the pancreas.Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5 (CCR5) into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol’s effects on acinar cells.