Ruxolitinib is a Janus kinase (JAK) 2 inhibitor that is an effective therapeutic agent for primary myelofibrosis (PMF), which helps significantly to reduce constitutional symptoms and spleen size. However, this drug has significant immunomodulatory effects that may lead to various opportunistic infections. Reactivation of tuberculosis and certain viral infections have been well documented. Although a few reports of patients with pulmonary cryptosporidiosis on ruxolitinib exist, an extensive literature review shows only one previously reported case of cryptococcal meningoencephalitis in an immunocompetent patient on ruxolitinib, with a history of avian exposure. Here we report another extremely rare incidence of cryptococcal meningitis in a fully immunocompetent male patient on ruxolitinib, with no history of contact with birds. Although this is an approved and effective therapy for PMF, careful evaluation, screening, and prophylaxis in susceptible individuals should be considered before starting therapy.