Objective: Leptospirosis and dengue fever (DF) are hard-to-differentiate diseases in cocirculating areas, especially during DF epidemics. Misdiagnosis and ensuing lack of antibiotic therapy can be detrimental in leptospirosis. The objective of this study was to identify factors that help differentiate acute leptospirosis from dengue fever on admission. Method: Patients with leptospirosis (positive serology or polymerase chain reaction) were compared with patients with DF (positive nonstructural 1 [NS1] antigen) in a case-control study with age matching. Data on admission were compared using bivariate analysis and multivariate analysis. Results: Seventy-two patients with leptospirosis were compared to 216 patients with DF. In bivariate analysis, the factors associated with leptospirosis were male gender, cough, anemia, and elevated blood levels of C-reactive protein (CRP), leukocytes, creatinine, bilirubin, and creatine phosphokinase. Exanthema, purpura, myalgia, headache, and neutropenia were associated with DF. In multivariate analysis, elevated blood levels of leukocytes, bilirubin, and CRP were associated with leptospirosis. The CRP threshold of 50 mg/L taken alone had elevated sensitivity and specificity. Conclusions: The CRP level, an easy-to-obtain biomarker, was a powerful tool to differentiate on admission leptospirosis and DF. Facing a dengue-like syndrome in cocirculating areas and awaiting new specific rapid diagnostic tests, CRP dosing could help the clinician to promptly consider the diagnosis of leptospirosis and initiate antibiotic therapy early.