No evidence-based information exists to guide clinicians for giving presumptive treatment to returning travelers when malaria is strongly suspected on clinical grounds but laboratory confirmation is not immediately available or is negative. A prospective study was conducted in travelers or migrants who sought care for fever to identify clinical and laboratory predictors of Plasmodium parasitemia. A total of 336 questionnaires were collected (97 malaria case patients and 239 controls). Multivariate regression analysis showed inadequate prophylaxis, sweating, no abdominal pain, temperature > or = 38 degrees C, poor general health, enlarged spleen, leucocytes < or = 10 x 10(3)/L, platelets < 150 x 10(3)/L, hemoglobin < 12 g/dL, and eosinophils < or = 5% to be associated with parasitemia. Enlarged spleen had the highest positive likelihood ratio for a diagnosis of malaria (13.6), followed by thrombopenia (11.0). Posttest probabilities for malaria were 85% with enlarged spleen and 82% with thrombopenia. A rapid assessment can thus help to decide whether a presumptive treatment should be given or not, especially when the results of the parasitological examination are not immediately available or are uncertain.