Background: The prospective prescription review system can improve prescription rationality, but its effectiveness in high-volume specialty care settings is not well established. Objective: We aimed to evaluate the effectiveness of the prospective prescription review system in reducing irrational prescriptions and to analyze factors associated with successful interception. Methods: This retrospective cohort study analyzed all outpatient and emergency prescriptions issued between January 1 and December 31, 2024, at an eye, ear, nose, and throat tertiary hospital in Shanghai, China. Among 2,559,342 prescriptions, 123,914 (4.84%) flagged as irrational by the prospective prescription review system were included. Results: The overall interception success rate was 32.99% (40,877/123,914). The prescription rationality rate increased from 95.23% (2,476,305/2,600,219) to 96.79% (2,477,144/2,559,342) after excluding intercepted prescriptions (