Abstract Purpose To assess whether the newly developed Comprehensive Chemotherapy Assistance Program (CAP) decreases errors and increases performance efficiency in ordering oncology medications as compared to the existing Computerized Physician Order Entry (CPOE) system, the Order Communication System (OCS). Methods All chemotherapy prescriptions ordered using OCS and CAP systems during the first year of CAP implementation were prospectively analyzed to identify near-miss cases. The efficiency outcomes were determined in a trial setting with eight predefined hypothetical chemotherapy regimens, each with four measures of the average time, movement distance on the screen, maximum input interval time, and number of mouse or keystrokes per order. A total of 14 physicians participated in the study, and each regimen was ordered twice, once using CAP and once using OCS. Results For all near-miss types, CAP orders showed significant improvements as compared with OCS orders (p<0.0001). For CAP orders, incorrect dose and agent errors were reduced by 43.9% and 31.6%, respectively. Compared with OCS orders, regimen defects, drug omissions, and incorrect data input errors were reduced by more than 70% for CAP orders. For all four efficiency measures, a statistically significant competence was identified when physicians ordered a chemotherapy prescription with CAP as compared with OCS (p<0.0001). Conclusions These results demonstrate the superiority of CAP over the existing CPOE system for ordering oncology medications with regard to safety and efficiency.