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Background: Dengue virus (DENV) infection is prevalent across tropical regions and may cause severe disease. Early diagnosis may improve supportive care. We prospectively assessed the Standard Diagnostics (Korea) BIOLINE Dengue Duo DENV rapid diagnostic test (RDT) to NS1 antigen and anti-DENV IgM (NS1 and IgM) in children in Cambodia, with the aim of improving the diagnosis of DENV infection. Methodology and principal findings: We enrolled children admitted to hospital with non-localised febrile illnesses during the 5-month DENV transmission season. Clinical and laboratory variables, and DENV RDT results were recorded at admission. Children had blood culture and serological and molecular tests for common local pathogens, including reference laboratory DENV NS1 antigen and IgM assays. 337 children were admitted with non-localised febrile illness over 5 months. 71 (21%) had DENV infection (reference assay positive). Sensitivity was 58%, and specificity 85% for RDT NS1 and IgM combined. Conditional inference framework analysis showed the additional value of platelet and white cell counts for diagnosis of DENV infection. Variables associated with diagnosis of DENV infection were not associated with critical care admission (70 children, 21%) or mortality (19 children, 6%). Known causes of mortality were melioidosis (4), other sepsis (5), and malignancy (1). 22 (27%) children with a positive DENV RDT had a treatable other infection. Conclusions: The DENV RDT had low sensitivity for the diagnosis of DENV infection. The high co-prevalence of infections in our cohort indicates the need for a broad microbiological assessment of non-localised febrile illness in these children. Author Summary: DENV infection first manifests as an undifferentiated fever before either settling without complications, or progressing to severe disease requiring inpatient admission and careful supportive intravenous fluid management. The ability to differentiate DENV infection from other febrile illnesses, and to predict those at risk of severe disease is likely to be important. We assessed the diagnostic accuracy of a commercially available DENV rapid diagnostic test (RDT) for children admitted with febrile illness to a hospital in Cambodia during the DENV transmission season. We found sensitivity of the DENV RDT to be 58% and specificity to be 85% versus reference assay DENV serology. We then modelled the ability of clinical features, basic laboratory parameters, and DENV RDT result at presentation of the child to distinguish DENV infection from other febrile illness, and determine the need for critical care admission. We found that the DENV RDT did not increase the accuracy with which we diagnosed DENV infection, and was not helpful in deciding which children required critical care admission. Indeed, the relatively high prevalence of serious bacterial disease in the cohort of children indicated a broad microbiological differential diagnosis in all febrile children, regardless of their DENV infection status. [ABSTRACT FROM AUTHOR]