Dengue virus (DENV) infection is associated with plasma leakage, which may progress to shock. The angiopoietin (Ang)-tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (Tie-2) axis regulates endothelial permeability. We examined the clinical utility of Ang-1, Ang-2, and the Ang-2-to-Ang-1 ratio for prediction of progression to severe DENV in a prospective cohort study of children and young adults (age 1 to <26 years) with DENV infection. Ang-1, Ang-2, Tie-2 were measured at presentation to an outpatient clinic in the Philippines from stored plasma by multiplex Luminex® assay. Patients were followed prospectively to document the clinical course (hospitalization, length of stay, intravenous fluid resuscitation, and transfer to a higher level facility). We included 244 patients (median age 9 years, 40% female). At presentation, 63 patients (26%) had uncomplicated dengue, 179 (73%) had dengue with warning signs, and 2 (0.82%) had severe dengue. One hundred eighty-one patients (74%) were hospitalized. Ang-1 levels were lower and Ang-2 higher in patients who required hospitalization. Ang-2-to-Ang-1 ratio >1 was associated with a relative risk of hospitalization of 1.20 (95% CI: 1.03-1.36, P = 0.016). A higher Ang-2-to-Ang-1 ratio was associated with longer length of hospital stay, higher frequency of transfer to a higher level facility, larger intravenous fluid requirement, hemoconcentration, and thrombocytopenia. Angiopoietin-2 was correlated with procalcitonin (Kendall's τ = 0.17, P = 0.00012), a marker of systemic inflammation, as well as soluble vascular cell adhesion molecule-1 (τ = 0.22, P <0.0001) and Endoglin (τ = 0.14, P = 0.0017), markers of endothelial activation. In conclusion, altered Ang-2-to-Ang-1 ratio can be detected early in the course of DENV infection and predicts clinically meaningful events (hospitalization, length of stay, and fluid resuscitation).