Introduction The incidence of acyclovir-induced hypersensitivity is rare. To our knowledge, there are four published case reports of oral acyclovir desensitization in adults. Evidence-based guidelines prompt the use of acyclovir for herpes simplex virus (HSV) prophylaxis and treatment. Literature on the cross-reactivity of structurally similar antiviral agents is conflicting, presenting a clinical challenge when choosing an alternative agent. This is a case of successful acyclovir desensitization in an allogeneic stem cell transplant patient. Case Report A 69-year-old female patient, diagnosed with myelodysplastic/myeloproliferative neoplasm, presented to the hospital for donor mismatch allogeneic bone marrow transplant. The patient reported acyclovir-induced angioedema while receiving treatment for non-complicated herpes zoster (shingles) infection. Management & Outcome: After the acyclovir oral desensitization was conducted in an ICU setting with 1:1 patient-nurse ratio, the patient was successfully started on acyclovir therapy, 800mg by mouth twice daily for HSV prophylaxis with no further complications. Discussion: Oral acyclovir desensitization can provide an option for HSV therapy in patients reporting severe allergy.