OBJECTIVES: The objectives of this study are to examine the clinical efficacy of using an oral (PO) acyclovir prophylactic herpes (HSV) protocol before a bone marrow transplant (BMT) versus the intravenous (IV) formulation of acyclovir, as well as the cost-savings that the oral formulation has relative to the intravenous. METHODS: Two retrospective cohorts were examined on the UCSF Medical Center Adult BMT/Leukemia Service. The first cohort consisted of 31 patients on the service for either a BMT or Peripheral Stem Cell Transplant (PSCT) in 1996. These patients were started on an IV acyclovir prophylactic protocol. The second cohort consisted of 41 patients on the same service for either a BMT or PSCT in 2001. These patients were started on an oral acyclovir prophylactic protocol. The two main outcome variables include cost per day of acyclovir treatment/prophylaxis and percentage stay on IV acyclovir. Further analyses conducted include subgroup analysis, sensitivity analysis, principal components analysis, linear regression, and an exploratory analysis. RESULTS: This study found that the oral protocol has similar clinical efficacy (2 infection in the PO group and 0 in the IV group) to the IV formulation, and that switching to the PO protocol significantly decreased the per day acyclovir cost, as well as the percentage of the patients' stay on IV acyclovir therapy relative to PO [$11.33 vs. $19.37 (p-value: 0.00001) and 33% vs. 89% (p-value: 0.00001), respectively]. A sensitivity analysis showed that if the infection rate had been greater, the changes in these variables would have still been significant. Adjusting for clinically interesting variables reinforced these results. However, subgroup analysis showed that the results were non-significant for two groups: (multiple myeloma and solid tumor). CONCLUSIONS: Oral acyclovir is a clinically safe and cost-saving method compared to IV acyclovir for HSV prophylaxis before a BMT.