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Polypharmacy is common among older patients and is linked to increased risk of adverse health outcomes. This study aimed to explore the association of polypharmacy and self-perceived health status (SPHS) among geriatric patients.This cross-sectional analysis of longitudinal observational research used national survey data from 2005–2008. Multivariate logistic regressions examined the likelihood of having a good/poor SPHS and polypharmacy. Medical Expenditure Panel Survey data provided by Agency for Healthcare Research and Quality were used in this study. Overall, SPHS was assessed using the Medical Expenditure Panel Survey health and well-being variable. Polypharmacy status was defined when patients were taking ≥5 medications.The study included a total of 102,309,656 weighted individuals reported from the survey of 4775 actual individuals from 2005–2008. Patients’ mean age was 74.7 years (standard error ± 0.138), and 58.1% were women, 87.3% were white, 55.2% were married, and 37.3% were from the southern region of the United States. Approximately 69.4% of patients reported polypharmacy. The most prevalent disease reported was hypertension (62.7%). We evaluated demographic and clinical characteristics based on SPHS and polypharmacy status. Overall, 78.09% of seniors reported their SPHS as good, whereas 21.91% reported their SPHS as poor. Among polypharmacy users, 72.52% reported good SPHS and 27.48% reported poor SPHS. Among older adults who were nonpolypharmacy users, 90.8% reported good and 9.02% reported poor SPHS. Logistic regression adjusted for demographic and socioeconomic factors showed that nonpolypharmacy users are approximately three times more likely to report their SPHS as good (odds ratio 2.75; 95% confidence interval 2.12–3.57, P < 0.001).Nonpolypharmacy users perceived their health status to be better than did polypharmacy users. Interventions to reduce polypharmacy may improve SPHS. One such intervention, medication reconciliation, may have a positive ripple effect on the patient-centered care delivery system.