A patient with systemic lupus erythematosus developed unexplained fever, nonregenerative anemia, leukopenia, and elevations in serum triglyceride and ferritin levels. Bone marrow studies established the diagnosis of macrophage activation syndrome with active hemophagocytosis. No infectious cause was found but pulmonary nocardiosis developed during the course of the disease. Intravenous gammaglobulin therapy was followed by a transient remission. Cyclophosphamide was given subsequently. In lupus patients, macrophage activation syndrome is exceedingly rare and has the same clinical, laboratory, and histologic features as those seen in patients with hemopathies, infections, or immune deficiencies. Investigations for an underlying infection are often negative, suggesting that the macrophage activation syndrome is due to lupus-related immune changes. Treatment is not standardized and relapses are common. This diagnosis should be considered in lupus patients with febrile pancytopenia.