OBJECTIVES: Neonatal herpes simplex virus (HSV) infections are associated with high mortality and long-term morbidity. However, incidence is low and acyclovir, the treatment of choice, carries risk of toxicity. We aimed to increase the percentage of patients 0 to 60 days of age who are tested and treated for HSV in accordance with local guideline recommendations from 40% to 80%. METHODS: This quality improvement project took place at 1 freestanding children's hospital. Multiple plan-do-study-act cycles were focused on interventions aimed at key drivers including provider buy-in, guideline availability, and accurate identification of high-risk patients. A run chart was used to track the effect of interventions on the percentage managed per guideline recommendations over time by using established rules for determining special cause. Pre- and postimplementation acyclovir use was compared by using a χ² test. In HSV-positive cases, delayed acyclovir initiation, defined as >1 day from presentation, was tracked as a balancing measure. RESULTS: The median percentage of patients managed according to guideline recommendations increased from 40% to 80% within 8 months. Acyclovir use decreased from 26% to 7.9% (P < .001) in non-high-risk patients but did not change significantly in high-risk patients (73%-83%; P 5 = .15). There were no cases of delayed acyclovir initiation in HSV-positive cases. CONCLUSIONS: Point-of-care availability of an evidence-based guideline and interventions targeted at provider engagement improved adherence to a new guideline for neonatal HSV management and decreased acyclovir use in non-high-risk infants. Further study is necessary to confirm the safety of these recommendations in other settings. [ABSTRACT FROM AUTHOR]