The ex vivo cytokine response to lipopolysaccharide (LPS) of whole blood from patients with typhoid fever was investigated. Tumor necrosis factor (TNF)-alpha release by LPS-stimulated blood was found to be lower during acute typhoid fever than after a course of antimicrobial therapy (P<or=.001). Ex vivo interleukin (IL)-1beta, but not IL-1 receptor antagonist, release was also depressed during the acute stage of typhoid fever. Low ex vivo production of TNF-alpha was associated with delayed recovery. No association was found between the TNFA-308 promoter polymorphism and LPS-induced TNF-alpha release, either during an active infection or after treatment. In acute typhoid fever, the ability of peripheral blood leukocytes to release proinflammatory cytokines in response to an inflammatory stimulus is depressed, and this may contribute to delayed recovery following antibiotic treatment.