BACKGROUND Herpes simplex virus (HSV) stromal keratitis with ulceration is one of the most serious forms of herpes corneal infection and is one of the most difficult conditions in terms of clinical management. We assessed the efficacy of intravenous acyclovir in the treatment of this condition. CASE REPORT Two cases of HSV stromal keratitis with ulceration were reported in terms of clinical presentation, investigation, treatment, and outcome.Diagnosis was confirmed by polymerase chain reaction (PCR) analysis. PCR testing of corneal scraping samples identified HSV-1 in the first patient and HSV-2 in the second patient. The first patient initially presented with herpes geographic epithelial keratitis and progressed to HSV stromal keratitis with ulceration during treatment with a prophylactic dose of oral acyclovir. Despite oral acyclovir therapy, the cornea lesion continued to worsen. The treatment was switched to intravenous acyclovir. The stromal infiltration gradually improved, and the epithelial defect closed. The second patient, who had undergone penetrating keratoplasty for 13 years, presented with extensive corneal infiltration and corneal melting. The laboratory work-up was positive for HSV-2, and intravenous acyclovir was prescribed. The patient's corneal infiltration improved, but a persistent epithelial defect was present. Then, 100% autologous serum was used until the epithelial defect closed. Prophylactic treatment with oral acyclovir was prescribed to both patients to prevent disease recurrence. CONCLUSIONS Intravenous acyclovir might be considered as an alternative treatment for patients with HSV stromal keratitis with ulceration who do not respond to oral acyclovir or those with an extensive infection on a corneal graft.