IMPORTANCE: Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially life-threatening reaction to medications with a mortality rate up to 10%. Standard therapy involves the use of systemic corticosteroids with tapering doses extending up to 9 months after the initial reaction. Alternative treatments for DIHS are needed, especially for patients for whom systemic corticosteroids are contraindicated. OBJECTIVE: To assess a short course of cyclosporine as first-line therapy for DIHS. DESIGN, SETTING, AND PARTICIPANTS: In this case series, 2 patients referred to the dermatology service of an academic tertiary care hospital and subsequently diagnosed as having DIHS were studied from December 1, 2013, through July 31, 2014. INTERVENTIONS: Short course (3-7 days) of cyclosporine. MAIN OUTCOMES AND MEASURES: Clinical and laboratory indicators were examined to determine the timing and efficacy of cyclosporine treatment. RESULTS: Two cases are reported of drug hypersensitivity reaction that were treated with cyclosporine, resulting in rapid and significant clinical improvement. The first case involved a woman in her 40s who developed DIHS after treatment with carbamazepine. A 7-day course of cyclosporine resulted in clinical resolution of the DIHS. The second case was that of a man in his 30s with minocycline-induced DIHS. A 3-day course of cyclosporine resulted in rapid and sustained clinical improvement. CONCLUSIONS AND RELEVANCE: A short course of cyclosporine was of therapeutic benefit in the treatment of 2 patients with DIHS. Short courses of cyclosporine in the acute care setting may be an alternative to longer courses of systemic corticosteroids in the treatment of DIHS.