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Background: In 2008 a nosocomial outbreak of five cases of viral hemorrhagic fever due to a novel arenavirus, Lujo virus, occurred in Johannesburg, South Africa. Lujo virus is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because of the remote, resource-poor, and often politically unstable regions where Lassa fever and other viral hemorrhagic fevers typically occur, there have been few opportunities to undertake in-depth study of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options typically available in industrialized countries. Methods and Findings: We describe the clinical features of five cases of Lujo hemorrhagic fever and summarize their clinical management, as well as providing additional epidemiologic detail regarding the 2008 outbreak. Illness typically began with the abrupt onset of fever, malaise, headache, and myalgias followed successively by sore throat, chest pain, gastrointestinal symptoms, rash, minor hemorrhage, subconjunctival injection, and neck and facial swelling over the first week of illness. No major hemorrhage was noted. Neurological signs were sometimes seen in the late stages. Shock and multi-organ system failure, often with evidence of disseminated intravascular coagulopathy, ensued in the second week, with death in four of the five cases. Distinctive treatment components of the one surviving patient included rapid commencement of the antiviral drug ribavirin and administration of HMG-CoA reductase inhibitors (statins), N-acetylcysteine, and recombinant factor VIIa. Conclusions: Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. Considering the high case-fatality and significant logistical impediments to controlled treatment efficacy trials for viral hemorrhagic fever, it is both logical and ethical to explore the use of the various compounds used in the treatment of the surviving case reported here in future outbreaks. Clinical observations should be systematically recorded to facilitate objective evaluation of treatment efficacy. Due to the risk of secondary transmission, viral hemorrhagic fever precautions should be implemented for all cases of Lujo virus infection, with specialized precautions to protect against aerosols when performing enhanced-risk procedures such as endotracheal intubation. Author Summary: Viral hemorrhagic fever is a syndrome often associated with high fatality and risk of secondary transmission. In 2008, an outbreak of a novel hemorrhagic fever virus called Lujo occurred in Johannesburg, South Africa, with secondary transmission from the index patient to four healthcare workers. Four of the five patients died. Lujo belongs to the arenavirus family and is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because most viral hemorrhagic fevers occur in remote, resource-poor settings, few in-depth controlled studies of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options are possible. We describe the clinical features of the five cases in this outbreak and summarize the clinical management, as well as providing additional epidemiologic detail. Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. The treatment options used in these five cases are discussed as well as the recommended precautions to prevent secondary transmission. [ABSTRACT FROM AUTHOR]