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Background: The differentiation of malaria from other causes of fever is difficult. The development of tools for rapid and specific clinical diagnosis is of paramount importance for the identification of individuals infected with malaria., Method: A 4-year prospective study to identify the clinical and biological variables associated with malaria included all patients suspected of having malaria who presented in the emergency department (ED) of a French hospital., Results: Of 783 patients admitted to the ED with suspected malaria, 145 had positive findings of a thick smear for Plasmodium species, mainly Plasmodium falciparum (90.3%). In univariate analysis, the following 12 variables were significantly associated with diagnosis of malaria: older than 30 years, male sex, immigration to France from an area where malaria is endemic, a visit to sub-Saharan Africa, insufficient antimalaria prophylaxis, fever, chills, absence of diarrhea, a leukocyte count within the reference range, thrombocytopenia, and increased lactate dehydrogenase and bilirubin levels. In multivariate analysis, the factors predictive of malaria included a visit to sub-Saharan Africa (odds ratio [OR], 7.7; 95% confidence interval [CI], 2.8-21.3), a temperature of at least 38.5 degrees C (OR, 6.2; 95% CI, 2.8-13.3), chills (OR, 3.0; 95% CI, 1.4-6.6), thrombocytopenia (OR, 16.5; 95% CI, 7.1-38.3), and abnormally high total bilirubin levels (OR, 21.5; 95% CI, 6.4-72.5). However, alone or combined, these features had insufficient sensitivity (95.0%) and low specificity (55.0%) for the diagnosis of malaria., Conclusions: Malaria should be suspected in all patients presenting with complaints after travel to an area where malaria is endemic, and these patients should undergo blood microscopy.