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Background: Dengue and malaria are two major public health concerns in tropical settings. Although the pathogeneses of these two arthropod-borne diseases differ, their clinical and biological presentations are unspecific. During dengue epidemics, several hundred patients with fever and diffuse pain are weekly admitted at the emergency room. It is difficult to discriminate them from patients presenting malaria attacks. Furthermore, it may be impossible to provide a parasitological microscopic examination for all patients. This study aimed to establish a diagnostic algorithm for communities where dengue fever and malaria occur at some frequency in adults. Methodology/Principal Findings: A sub-study using the control groups of a case-control study in French Guiana – originally designed to compare dengue and malaria co-infected cases to single infected cases – was performed between 2004 and 2010. In brief, 208 patients with malaria matched to 208 patients with dengue fever were compared in the present study. A predictive score of malaria versus dengue was established using.632 bootstrap procedures. Multivariate analysis showed that male gender, age, tachycardia, anemia, thrombocytopenia, and CRP>5 mg/l were independently associated with malaria. The predictive score using those variables had an AUC of 0.86 (95%CI: 0.82–0.89), and the CRP was the preponderant predictive factor. The sensitivity and specificity of CRP>5 mg/L to discriminate malaria from dengue were of 0.995 (95%CI: 0.991–1) and 0.35 (95%CI 0.32–0.39), respectively. Conclusions/Significance: The clinical and biological score performed relatively well for discriminating cases of dengue versus malaria. Moreover, using only the CRP level turned to be a useful biomarker to discriminate feverish patients at low risk of malaria in an area where both infections exist. It would avoid more than 33% of unnecessary parasitological examinations with a very low risk of missing a malaria attack. Author Summary: The authors present a retrospective matched-pair study on dengue and malaria performed in French Guiana. These two infections are major public health concerns in tropical regions, especially in South America and Southeast Asia, where they affect neglected populations which makes them interesting to be published in a journal aiming to publish about neglected tropical diseases. Although the pathogeneses of these two arthropod-borne differ, their clinical and biological presentations are unspecific. During dengue epidemics, hundreds of patients are admitted weekly with diffuse pains and fever at the emergency room. Among them, it is difficult to accurately distinguish malaria attacks, which are far less frequent than dengue fever cases. Moreover, it may be impossible to provide a parasitological microscopic examination for all patients. We believe the results of the present study, based on a sample of n = 416 individual are worthwhile as they support evidence that biological factors can help to discriminate between the two, in areas where they co-exist in endemic areas. A simple prognostic score based on clinical and biological criteria was built, interesting and easy-to-use for physicians in tropical areas. [ABSTRACT FROM AUTHOR]