BACKGROUND Hemophagocytic histiocytic syndrome (HHS) generally occurs in immunocompromised patients and often has a rapidly fatal course. HHS may be cured by treatment of the underlying disorder, especially when it is triggered by an infection. If no cause has been found, no therapy is known and outcome is poor. The aim of this study was to investigate the clinical course and response to intravenous immunoglobulin treatment in renal transplant patients diagnosed with HHS. METHODS Thirteen patients who were diagnosed with HHS between 1995 and 2003 were retrospectively assessed. The mean age of HHS patients was 38.6 +/- 10 years (5 women, 8 men). RESULTS Median time to onset of symptoms after renal transplantation was 15.1 +/- 12.1 months (range 0.5-30 months). The first 2 patients in whom no etiologic factor was found were seen before 1998 and died due to multiorgan failure. HHS was related to an infectious etiology in 6 of 13 patients: tuberculosis (n=3), cytomegalovirus (CMV) infection (n=2), Escherichia coli (E. coli)-associated septicemia (n=1), but HHS was cured by antimicrobial therapy in only 2 of them (1 with tuberculosis, the other with E. coli-associated septicemia). After June 1998, high-dose immunoglobulin (IVIg) therapy was used in 6 patients. HHS was related to an infectious etiology in 2 patients unresponsive to antimicrobial treatment, and of unknown etiology in 4 patients. All of them completely recovered. Before 1998, 2 patients unresponsive to antimicrobial therapy (1 with tuberculosis, the other with CMV) died. They were not given IVIg. CONCLUSIONS We concluded that when HHS does not respond to treatment of the underlying infection, or is of unknown etiology in immunocompromised patients, high-dose IVIg therapy should be administered.