Background Emergency medicine (EM) pharmacists may be uniquely positioned to optimize discharge prescriptions for emergency department (ED) patients but the clinical significance of interventions and association with patient outcomes are not well-described. Objective To evaluate the clinical significance of EM pharmacist interventions completed during review of ED discharge prescriptions. Setting This study was conducted in an academic medical center ED. Methods: This was a retrospective observational study of patients discharged with prescriptions from the ED over two months. EM pharmacists reviewed discharge prescriptions and provided drug therapy recommendations. Two independent reviewers rated the clinical significance of interventions. High risk criteria were proposed a priori and included in a multivariable logistic regression analysis to identify variables independently associated with pharmacist intervention. Main Outcome Measure The primary outcome measure was the rate, type, and clinical significance of interventions associated with EM pharmacist review of discharge prescriptions. Results A total of 3107 prescriptions for 1648 patients were reviewed. Interventions occurred for 7.3% of patients with 29% of interventions rated as significant. The intervention rate was higher in patients with at least 1 high risk criteria versus those without (9.6% vs. 3.7%, p < 0.0001). An incremental increase in the number of discharge prescriptions was independently associated with pharmacist intervention. The 30 day readmission rates did not differ between patients with and without pharmacist review (27.4% vs. 26.2%, p = 0.38). Conclusion: Pharmacist review of discharge prescriptions resulted in clinically significant interventions but did not impact readmission rates. An incremental increase in the number of discharge prescriptions was associated with pharmacist intervention.