Invasive fungal infection can be a lethal complication in systemic lupus erythematosus (SLE). Crytococcus neoformans, as one of the most common pathogenic species worldwide, can cause infection disease in human. The central nervous system (CNS) is a common site for cryptococcal infection which usually presents cryptococcal meningitis. The cryptococcal meningitis is a recognized complication of SLE, with high mortality rates, particularly in those treated with immunosuppressive agents. However, it is difficult to differentiate infectious meningitis and neuropsychiatric lupus because of the clinical manifestations are unspecific and frequently are confused with lupus activity. So a early diagnosis and treatment is very important for its significant mortality and morbidity. We report the case of fatal meningoencephalitis by Cryptococcus neoforman in a 44 years old patient with SLE