In infection-associated hemophagocytic syndrome (HPS) the causative pathogen is often undetected, except in cases of herpes virus infections. We describe a 12-year-old girl with life-threatening pneumonia with HPS caused by an adenovirus. She was admitted with complaints of persistent fever and systemic petechiae/purpura. The day after admission the patient developed sudden dyspnea with massive infiltration of the bilateral lower lung field. She exhibited coagulopathy, hepatic dysfunction, and remarkable elevations in serum levels of cytokine, ferritin, and urinary beta2-microglobulin. A diagnosis of HPS was made, and the patient was treated with dexamethasone and cyclosporin A on the second hospital day. Her fever went down quickly, and the abnormal laboratory and chest radiographic findings returned to normal over a period of 2 weeks. Antibody analysis was not successful in identifying the pathogen responsible. However, a polymerase chain reaction (PCR) assay of lung tissue biopsied on the fifth hospital day was positive for an adenovirus (subgroup B), and quantitative adenoviral DNA analysis by real-time PCR using primers covering serotypes 3, 7,11, and 35 (all subgroup B) confirmed this initial finding (93 copies/microg DNA in the biopsied lung and no detectable adenovirus DNA in the lung tissues of control subjects). This approach may provide important clues for improving outcomes and clarifying the exact etiology in cases of often fatal, infection-associated HPS.