OBJECTIVES: Polypharmacy (≥5medications) is common among older patients (˃65 old) and is linked to increased risk of adverse health outcomes resulting in hospitalizations and sometimes death. This study aims to explore the association of polypharmacy and self-perceived health status (SPHS) among geriatric patients. METHODS: This longitudinal observational research used Medical Expenditure Panel Survey household component (MEPS-HC), a national survey data from 2005-2008. National estimates on individuals were estimated using longitudinal weights provided by MEPS. Overall SPHS was assessed using the MEPS health and well-being variable. Multivariate logistic regressions examined likelihood of having a “Good” or “Poor” SPHS and polypharmacy (≥5medications). RESULTS: Study included a total of 102,309,656 weighted individuals reported from survey of 4775 actual individuals from 2005-2008. Patient’s mean age was 74.7 years (SE±0.138) 58.1% women, 87.3% Caucasian, 56.8% married, 37.8% were from the southern region of USA.  About 69% of patients reported polypharmacy. The most prevalent disease reported was hypertension (62.7%). Overall, 78% of seniors reported SPHS as “Good” while 22% reported SPHS as “Poor”. Among polypharmacy users, 72.52% reported “Good” SPHS; 27.48% for “Poor” compared to non-polypharmacy seniors who reported 90.8% “Good” and 9.02% for “Poor”. Logistic regression adjusted for covariates showed that non-polypharmacy users are about three times more likely to report SPHS as “Good” (OR=2.73;95%CI:2.11– 3.54;P=0.000001). CONCLUSIONS: We observed significant differences in baseline characteristics and SPHS between polypharmacy and non-polypharmacy users. Non-polypharmacy users perceived their health status to be better than polypharmacy users. Mediation reconciliation among older patients may prevent polypharmacy and improve health status.