Introduction Our objective was to determine the relationship between polypharmacy (treatment with prescription drugs from 6 or more drug classes concurrently) andhealth-relatedquality of life (HRQoL) among US adults with arthritis. Methods We conducted a retrospective cohort study that used2-year longitudinal data from the Medical Expenditure Panel Survey to analyze a cohort of 6,132 adults aged over 21 years with arthritis. Measures of HRQoL were the summary scores from the mental component summary (MCS) and physical component summary (PCS) of the12-itemshort-formhealth survey. Unadjusted and adjusted regression models were used to evaluate the association between polypharmacy and HRQoL measures. We used SAS, version 9.4, (SAS Institute Inc) to conduct all analyses. Results In unadjusted analyses, adults with arthritis taking prescription drugs from 6 or more drug classes concurrently had significantly lower MCS and PCS scores (β, -3.11, P < .001 and β, -10.26, P < .001, respectively) than adults taking prescription drugs from fewer than 6. After controlling for the demographic characteristics, number of mental and physical chronic conditions, and baseline MCS and PCS scores, adults taking prescription drugs from 6 or more drug classes concurrently had significantly lower PCS scores (β, -1.68, P < .001), than those taking prescription drugs from fewer than 6. However, no significant difference in MCS scores was found between adults taking prescription drugs from 6 or more drug classes concurrently and those taking prescription drugs from fewer than 6 (β, -0.27, P= .46). Conclusion Polypharmacy is significantly associated with lower PCS scores among adults with arthritis. Because polypharmacy can lead to drug-drug and drug-disease interactions, health care providers need to consider the risk and adopt a cautious approach in prescribing multiple drugs to manage chronic conditions and in choosing therapies to improve HRQoL among adults with arthritis.