OBJECTIVE. The goal was to determine whether implementation of a computerized physician order entry system was associated with a decrease in medication administration variances in a NICU. METHODS. A prospective observational study was conducted. Research nurses recorded details of medication administrations for patients in a NICU during standardized observation periods. Details of each administration were compared with the medication order; a variance was defined as a discrepancy between the order and the medication administration. Rates of variances before and after implementation of computerized physician order entry in the NICU were compared. Specific types of and reasons for variances were also compared. RESULTS. Data on 526 medication administrations, including 254 during the pre-computerized physician order entry period and 272 after implementation of computerized physician order entry, were collected. Medication variances were detected for 19.8% of administrations during the pre-computerized physician order entry period, compared with 11.6% with computerized physician order entry (rate ratio: 0.53). Overall, administration mistakes, prescribing problems, and pharmacy problems accounted for 74% of medication variances; there were no statistically significant differences in rates for any of these specific reasons before versus after introduction of computerized physician order entry. Administration of a medication at the wrong time accounted for 53.1% of all variances. Variance rates related to giving a drug at the wrong time were significantly lower in the computerized physician order entry period than in the pre-computerized physician order entry period (rates: 6.7% and 9.9%, respectively; rate ratio: 0.53). CONCLUSIONS. Implementation of computerized physician order entry in a NICU was associated with a significant decrease in the rate of medication administration variances. However, even with the use of computerized physician order entry, variances were noted for >11% of all medication administrations, which suggests that additional methods may be needed to improve neonatal patient safety. Copyright © 2008 by the American Academy of Pediatrics.