Polypharmacy is a well-described problem in the geriatric population. It is a relatively new problem for people living with HIV (PLWH), as this group now has a life expectancy approaching that of the general population. Defining polypharmacy for PLWH is difficult, since the most common traditional definition of at least five medications would encompass a large percentage of PLWH who are on antiretrovirals (ARVs) and medications for other medical comorbidities. Even when excluding ARVs, the prevalence of polypharmacy in PLWH is higher than the general population, and not just in resource-rich countries. Using a more nuanced approach with "appropriate" or "safer" polypharmacy allows for a better framework for discussing how to mitigate the associated risks. Some of the consequences of polypharmacy include adverse effects of medications including the risk of geriatric syndromes, drug-drug interactions, decreased adherence, and over- and undertreatment of medical comorbidities. Interventions to combat polypharmacy include decreasing pill burden-specifically with fixed-dose combination (FDC) tablets- and medication reconciliation/deprescription using established criteria. The goal of these interventions is to decrease drug interactions and improve quality of life and outcomes. Some special populations of interest within the community of PLWH include those with chronic pain, substance abuse, or requiring end of life care. A final look into the future of antiretroviral therapy (ART) shows the promise of possible two-drug regimens, which can help reduce the above risks of polypharmacy.