OBJECTIVE: To assess the prevalence of potential drug-drug interactions (pDDIs) among polypharmacy patients in Jordan using Lexicomp®. Additionally, this study aims to categorize and rate the identified pDDIs according to interaction risk, severity, and reliability. METHODS: A descriptive cross-sectional study was conducted at six different hospitals representing different public health sectors in Jordan (ministry of health, royal medical services, and university-affiliated hospitals). Polypharmacy patients from outpatient clinics (e.g., cardiology,& and internal medicine) were identified, recruited, and interviewed by clinical pharmacists. pDDIs were assessed using the Lexicomp® mobile application and classified according to interaction risk rating, severity, and reliability rating. Furthermore, the prevalence of pDDIs across chronic medical conditions was assessed. P-value <0.05 was considered as significant. RESULTS: A total of 801 patients with polypharmacy were identified. The average number of drugs per patient was 6.6 ± 1.96, with an average of 4.2 ± 3.0 pDDIs per patient. Potential drug-drug interactions were detected in 769 patients (96%), with a total of 3359 interactions. Blood pressure lowering agents were involved in 39.9% of the pDDIs. Cardiovascular system drugs contributed to the largest share of pDDIs (46.6%). While diuretics had the major share of interactions among cardiovascular system drugs (16.2%), drugs used in diabetes had the highest share across all groups (17.1%). The majority of pDDIs were of "C" risk rating with a moderate interaction severity, whilst 1.6% of pDDIs could have been avoided in the first place as the concurrent administration of these agents is contraindicated (i.e., risk rating X). Patients with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, gout, and chronic kidney disease were associated with the highest number of potential drug-drug interactions. CONCLUSION: Our study showed that 96% of polypharmacy patients at outpatient clinics have at least one pDDI. Almost half of the detected interactions involved cardiovascular medications. The majority of these pDDIs had moderate severity, with no more than 10% of the interactions requiring therapy modification.