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As HIV-infected patients aged 50 years or older are at increased risk of comorbidities and multidrug treatments, we examined their exposure to the potential drug–drug interactions (PDDIs) of antiretroviral (ARV) and other medications.This cross-sectional study involved the patients aged 50 years or older receiving ARV and non-ARV medications at our clinic. PDDIs were identified using the University of Liverpool HIV Drug Interaction Checker. Logistic regression models were used to assess risk factors for PDDIs. The American Geriatrics Society Beers Criteria were used to identify potentially inappropriate medications (PIMs).A total of 395 (53.9%) of 744 patients showed ≥1 PDDI: 47.4% ≥ 1 amber-PDDI (comedications requiring appropriate management) and 5.6% ≥ 1 red-PDDI (contraindicated comedications). A higher risk of PDDIs was associated with the use of ≥5 medications (P < 0.001), of antiosteoporotics (P < 0.001), calcium channel blockers (P < 0.001), anti–benign prostatic hypertrophy agents (P < 0.001), hypnotics/sedatives (P = 0.022), and anticoagulants (P = 0.006). A higher risk of red-PDDIs was associated with the use of antacids (P < 0.001), anti–benign prostatic hypertrophy agents (P < 0.001) and antipsychotics (P = 0.023). The use of nucleoside reverse transcriptase inhibitor + nonnucleoside reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor rather than protease inhibitor–based regimens was associated with a reduced risk of PDDIs (P < 0.001). Overall, 119 (16.0%) patients were receiving PIMs (mainly hypnotics/sedatives) and 49 (41.2%) of them had PDDIs able to increase the blood levels of these medications.Older patients with HIV are highly exposed to PDDIs between ARVs and comedications. The knowledge of their complete medication regimens and the screening for PDDIs and PIMs is therefore crucial to prevent drug-related adverse outcomes in this population.