OBJECTIVE: There are two different types of chronic active Epstein-Barr virus (CAEBV) infection: chronic EBV (CEBV) having persistent infectious mononucleosis (IM)-like illness with relatively good prognosis, and severe CAEBV (SCAEBV)infection that has rather severe manifestations and generally poor prognosis with many life-threatening complications, such as EBV-associated malignant lymphoma and hemophagocytic syndrome (HPS). The purpose of this study was to clarify the clinical and prognostic characteristics in 12 cases with SCAEBV infection. METHOD: Data of 12 cases with SCAEBV infection were analyzed retrospectively, which included clinical and auxiliary examination, pathological data, especially EB virus (EBV)-antibodies and DNA in peripheral blood mononuclear cells (PBMC) and infected tissue, and follow-up information. RESULT: Of the 12 cases, 7 were male and 5 were female. The age at the onset of diseases ranged from 35 months to 14 years (median, 11 years). The major manifestations were fever (100%), splenomegaly (91.7%), hepatomegaly (83.3%), lymphadenopathy (75.0%), and others, including skin rash, development retardation, jaundice, ascites, pulmonary hypertension, oral ulcer, cholecystitis and pleural effusion. The abnormalities of auxiliary examination were as follows: elevated LDH level (91.7%), liver dysfunction (83.3%), anemia (75.0%), leukopenia (58.3%), neutropenia (50.0%), thrombocytopenia (25.0%) and abnormal chest X-ray findings. At the time of onset, 58.3% of the patients had an IM-like illness. In all of the 12 cases, EBV serologic tests revealed high IgG antibody levels against EB viral capsid antigen (VCA). The patients often had positive IgM and IgA antibodies against VCA (33.3% and 66.7%) as well. Elevated IgG antibody level to early antigen (EA) (100.0%), occasionally positive IgA antibody (40.0%) were also seen. The mean load of EBV-DNA detected by real-time polymerase chain reaction (PCR) in the PBMC was (8.12 x 10(6), median)copies/ml. Four of 12 cases presented a poor clinical course, two of whom died from EBV-associated HPS, 1 from severe multiple pathogens infection, and 1 from multiple organ failure. In addition, 1 case developed Hodgkin's T cell lymphoma and another case showed hepatopulmonary syndrome in 2 years after splenectomy. CONCLUSIONS: The clinical feature of SCAEBV infection varied exceedingly. EBV-DNA load in PBMC of SCAEBV infected patients was significantly increased. More attention should be paid to the disease because of its severe complications, poor prognosis and high mortality.