Older persons with HIV (PWH) with comorbidities may experience increased perceived pill burden - a subjective experience of the demands associated with taking medications to sustain their health. The objective of this analysis was to examine the demographic, psychosocial, and HIV-related clinical factors associated with perceived pill burden in a sample of middle-aged and older PWH. Data came from men with HIV (MWH) aged ≥ 40 years from the Multicenter AIDS Cohort Study. Dependent variables were: [1] Pill frequency burden (“The number of times each day I am supposed to take my pills is too often”) and [2] pill quantity burden (“The total number of pills I am supposed to take is too much”) were assessed and dichotomized as “Agree” (indicating burden) versus a combined category of “Neither Agree/Disagree” and “Disagree” (indicating no burden). Participants (n = 586) had a median age of 59 years (IQR: 54–65), with 56.8% identifying as White non-Hispanic. In adjusted logistic regression model, significant depressive symptoms – defined as CES-D scores ≥ 16 – were significantly associated with increased odds of perceived pill frequency burden (aOR: 2.79; 95% CI: 1.14–6.84) and perceived pill quantity burden (aOR: 2.08; 95% CI: 1.09–3.95). Higher counts of HIV and non-HIV medications were also positively associated with greater odds of pill burden. These findings suggest the need for regular screening for perceived pill burden and depression for older MWH managing HIV and multiple chronic conditions. Additional research employing longitudinal designs is essential to examine the long-term history of perceived pill burden.