Author Summary Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal medical condition that can occur after a patient has an infection. While HLH is most commonly associated with Epstein-Barr virus infections, it has been reported as a complication of dengue, a common mosquito-borne, acute febrile illness. After a cluster of pediatric dengue-associated HLH patients was identified in Puerto Rico, active surveillance and a case-control investigation was conducted to determine the rate of HLH in children and identify risk factors for HLH following dengue. During 2008–2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Most (91%) dengue-associated HLH patients had illness onset during the 2012–2013 epidemic, however, HLH was not found to be associated with a particular type of dengue virus. Dengue-associated HLH cases were younger than dengue inpatient controls, were hospitalized longer, and were admitted more frequently to the pediatric intensive care unit. Cases had longer duration of fever, and were more likely to have anemia, hepatomegaly and elevated liver transaminases than controls. Physicians in the tropics should be aware that HLH may complicate dengue, and they should evaluate dengue patients who develop anemia and severe liver injury.