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Polypharmacy or the concomitant use of five or more medications, which is one of the common problems among the elderly in Thailand, profoundly impacts on patients’ morbidity and mortality. Therefore, the objective of this study is to determine related risk factors to polypharmacy and associated drug-related problems (DRPs) with polypharmacy in order to increase healthcare personnel’s awareness, resulting in prevention and reduction of polypharmacy. This study was a cross-sectional study which the subjects were categorized into three groups based on definition such as the excessive polypharmacy group (>9 medications), the polypharmacy group (5-9 medications) and the no polypharmacy group (< 5 medications). Four hundred and fifty two recruited participants aged 60 years or over visited the Internal Medicine Outpatient Clinic of Ramathibodi Hospital, during the period from December 1st, 2015 to May 31st, 2016. The prevalence of polypharmacy was 74.8%. A multivariate multinomial logistic regression analysis to identify significant risk factors (no polypharmacy group as reference) revealed that odds ratio was presented strongest factor with the excessive polypharmacy group including diabetes mellitus (OR 3.61, 95% CI: 1.86-7.02; P < 0.001). Furthermore, the study revealed that three most common associated DRPs with polypharmacy were drug-drug interactions (DDIs) (91.4 %), unnecessary medications (72.4 %) and potentially inappropriate medications (PIMs) (62.9 %). Therefore, physicians should concern associated factors as well as appropriate drug administration to prevent polypharmacy.