Cryptococcus neoformans is an opportunistic fungal infection affects predominately the central nervous system in HIV patients and patients with other immunocompromised states. It has rarely been described in immunocompetent patients. It is a serious infection with a high of mortality rate. We describe a case of a 48-year-old patient diagnosed with lupus nephritis treated with corticosteroids and mycophenolate mofetil who developed central nervous cryptococcosis complicated by septicemia. She died despite the use of antifungals. Cryptococcal infection is an uncommon, but often a fatal complication of systemic lupus erythematosus. Timely diagnosis and effective antifungal therapy could improve its prognosis.