Aim: The primary aim of the study is to analyze prevalence of polypharmacy, determine factors affecting polypharmacy and identify potential Drug Related Problems (DRPs) in patients with chronic kidney disease (CKD). Methods: A prospective observational study was conducted among 207 patients diagnosed with chronic kidney disease in a tertiary care hospital for a period of 6 months. Drug-Related Problems were identified, reported and categorized in accordance with the Helper and Strand, 1990 Classification. Binary logistic regression was used to identify the association between dependent variable and independent variables. Result: The mean age of the study population was 56.64 ±16.64 with male predominance (66%). The prevalence of polypharmacy was 76.8% and prescription pattern was analyzed in different stages of chronic kidney disease was found to be antiulcer drugs (84.5%) and antihypertensive (81.6%) were the most commonly prescribed class of drug. Age, gender, length of hospital stay, comorbidities such as diabetes mellitus and hypertension were determined as the main predictors for polypharmacy (p-value < 0.05). Drug interaction (93.2%) was identified as main Drug-related problem associated with polypharmacy (p-value of 0.022). Conclusion: Polypharmacy has a positive correlation with advancement of chronic kidney disease which put them at higher risk for drug-related problems. Drug Related Problems may be prevented or reduced by early detection and modification of the above-mentioned predictors.