We present a case report of cryptococcal immune reconstitution syndrome (IRS), in a non HIV infected patient, which we treated with hydroxychloroquine with successful results. We briefly review cryptococcal IRS, possible mechanisms of action of hydroxychloroquine as an immunomodulatory agent, and its potential role in management of IRS. (C) 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.