To describe a case series of patients with unilateral, posterior interstitial keratitis presumed to be caused by herpes simplex virus.Retrospective case series.Five patients were found to have unilateral, posterior interstitial keratitis. Three of the involved eyes had decreased corneal sensation, and 2 eyes had corneal stromal neovascularization. All patients were treated with topical steroids and an oral antiviral, and among those with long-term follow-up, clinical improvement required treatment over an extended duration. A review of the literature revealed 1 reported case with a similar clinical appearance, although that case was attributed to Lyme disease.The clinical presentation of unilateral, posterior interstitial keratitis may be a rare manifestation of herpes simplex virus keratitis.