Objective Estimates of polypharmacy among US adults with systemic lupus erythematosus (SLE)—a relatively young and disproportionately minoritized population—remain sparse. We sought to estimate the prevalence of polypharmacy in SLE and identify the most common medications used. Methods For this cross‐sectional study, participants were recruited from a population‐based cohort of adults with validated SLE in Atlanta, Georgia. Prescription and over‐the‐counter (OTC) medications were self‐reported at the study visit. Polypharmacy was defined as five or more prescription or OTC medications. Estimates of polypharmacy prevalence by key sociodemographic and SLE‐related participant characteristics were obtained using crude logistic regression and postestimation marginals. Results More than half (56.3%) of participants (n = 451; 15.3% ≥60 years old, 91.8% women, and 81.8% Black) reported polypharmacy. Older age (68.1%, 59.8%, and 43.0% for ages ≥60 years, 40–59 years, and 18–39 years), higher vs lower disease activity (65.8% vs 46.2%) and cumulative SLE‐related damage (68.5% vs 42.4%), longer disease duration (62.4% vs 50.0%), and taking three to five vs zero to one immunomodulating medications (79.6% vs 38.0%) were associated with higher age‐adjusted prevalence of polypharmacy; prevalence was not statistically significantly different by sex, race, or education. Although hydroxychloroquine (71.4%), glucocorticoids (44.3%), and other immunomodulating drugs (50.3%) were common, polypharmacy was most often driven by other medications, such as antihypertensives (61.9%), nonopioid pain relievers (51.7%), allergy treatments (22.4%), antidepressants (22.2%), and gastric reflux medications (21.7%). Conclusion Our results underscore the need to address the burden of medication regimens in this population through individualized medication optimization strategies that account for prescription and OTC medications used by those with SLE.

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