Cryptococcal meningitis is a rare occurrence in systemic lupus erythematosus (SLE). The risk factors of developing this infection are duration of SLE, intensity of glucocorticoid use, and SLE-related intrinsic immune abnormalities. Early recognition and prompt initiation of antifungals can prevent complications and improve survival. There is a dearth of evidence with regards to optimal treatment of cryptococcosis in non-HIV infected and non-transplant patients. The general consensus is to follow treatment guidelines for HIV-positive patients with cryptococcal meningitis. We describe a girl with active SLE and cryptococcal meningitis, and discuss the diagnostic and therapeutic challenges faced in this case.