Objective: Polypharmacy (prescription of minimum 5 drugs/day) is often encountered in chronic kidney disease (CKD) patients due to their high number of comorbidities. Thus, a vicious cycle is born: the prescription of more drugs can lead to drug-drug (DDI) or food-drug interactions (FDI) and adverse effects mistakenly considered new comorbidities and treated with new medications. We evaluated polypharmacy use and the potential risk of DDI/FDI in Romanian CKD patients. Design and method: Retrospective, observational study in an internal medicine clinic. Data were extracted from medical records of patients attending the clinic in a two-month period in 2018. Patients were divided into CKD patients and controls (patients diagnosed with a different disease other than CKD). DDI/FDI were checked via the Drug Interactions Checker. The hospital's ethics council approved the study (approval 4263/13.05.2019). Written informed consent was collected from all patients. Regulations imposed by the national law/Declaration of Helsinki [1975&2008(5) revised] were respected. We presented categorical variables as frequencies/percentages and continuous variables as mean±standard deviation. Continuous variables were compared via independent samples t-tests. Categorical variables were compared using Fisher's exact test. The level of significance was set at 5% and presented as p-values. The analysis was performed using GraphPadQuickCalcs. Results: Study group: 22 CKD patients, 72.72 ± 10.37 years, range 54–93 years, 54.55% males. Controls: 144 patients, 67.90 ± 13.31 years, range 22–92 years, 52.77% females. CKD patients had more comorbidities (P = 0.0001) and drug prescriptions at discharge (P = 0.005) versus controls. Polypharmacy was noted in 95.45% (N = 21) of CKD patients versus 74.30% (N = 107) of controls (P = 0.02). CKD patients were at a higher risk of DDI (P = 0.01) and especially major and moderate DDI (P = 0.005 and P = 0.02, respectively) versus controls. CKD patients had a similar risk of potential FDI and DDI to controls (Table 1). The most frequent potential DDI and FDI interactions in CKD patients are depicted in Table 2. Conclusions: Polypharmacy is a serious reason for concern in CKD patients. Their management should be targeted at reducing medication burden and revised to include only drugs with low DDI/FDI risks. Patients should be carefully monitored and informed regarding the risks posed by polypharmacy.