Dengue is caused by infection with any of four mosquito-transmitted dengue viruses (DENV-1-4) and is characterized by fever, headache, myalgia, and leukopenia. Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome that can be familial or acquired, and is characterized by persistent fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. Acquired HLH is most frequently associated with Epstein Barr virus infection but also has been associated with dengue. This report describes a fatal case of acquired HLH that was apparently triggered by infection with DENV-3. The patient developed an acute febrile illness in August 2012 during a 1-month vacation in New Mexico. After returning to her home in Texas, she was initially diagnosed with West Nile virus (WNV) infection, developed pancytopenia, liver failure, and disseminated intravascular coagulopathy, and died. DENV-3 was detected in a premortem bone marrow biopsy in which erythrophagocytosis was evident. This case underscores the need for clinicians in the United States to be vigilant for dengue and request diagnostic testing for suspected cases, which should be reported to public health authorities.