Differential diagnosis of fever in travelers returning from the tropics is extremely diverse. Apart from the travel destination, other diagnostic predictors of tropical infections are poorly documented in returning travelers. From April 2000 to December 2005, we prospectively enrolled all patients presenting at our referral centers with fever within 1 year after visiting a tropical or subtropical area. For clinical relevance, the diagnostic predictors of the leading tropical conditions were particularly investigated in the febrile episodes occurring during travel or within 1 month after return (defined as early-onset fever). In total, 2071 fever episodes were included, occurring in 1962 patients. Most patients were western travelers (60%) or expatriates (15%). Regions of exposure were mainly sub-Saharan Africa (68%) and southern Asia/Pacific (14%). Early-onset fever accounted for 1619 episodes (78%). Most tropical infections were related to specific travel destinations. Malaria (mainly Plasmodium falciparum) was strongly predicted by the following features: enlarged spleen, thrombocytopenia (platelet count <150 x 10(3)/microL), fever without localizing symptoms, and hyperbilirubinemia (total bilirubin level >or=1.3 mg/dL). When malaria had been ruled out, main predictors were skin rash and skin ulcer for rickettsial infection (mainly African tick bite fever); skin rash, thrombocytopenia, and leukopenia (leukocyte count <4 x 10(3)/microL) for dengue; eosinophil count >or=0.5 x 10(3)/microL for acute schistosomiasis; and enlarged spleen and elevated alanine aminotransferase level (>or=70 IU/L) for enteric fever. The initial clinical and laboratory assessment can help in selecting appropriate investigations and empiric treatments for patients with imported fever.