Introduction and Objectives: Nontyphoidal Salmonellae (NTS) are a major cause of bacteraemia in Sub-Saharan Africa. Most cases of NTS bacteraemia in this region occur in children under five years of age and HIV-infected adults. The objectives of this work were to investigate the role of antibody in immunity against NTS in Africans and to explore the potential of measuring anti-Salmonella antibody as the basis of a diagnostic assay. Materials and Methods: We obtained blood from healthy Malawians of all ages and NTS bacteraemic children. Invasive strains of NTS were from bacteraemic Malawian children. We measured anti-Salmonella antibody levels by flow cytometry and we assessed the ability of serum to kill Salmonella in a serum bactericidal assay. Phagocytic cell function of peripheral blood cells in relation to NTS was examined by flow cytometric oxidative burst and phagocytosis assays and a blood cell killing assay. Serum cytokine levels were measured using a cytokine bead array assay. Results: We developed and optimised a flow cytometric assay that measured antiSalmonella antibody titres over 4 log-decades of fluorescence. Using this assay in a crosssectional study of healthy Malawians, we found that anti-Salmonella antibody titres increased with age with no reduction in old age. Oxidative burst by peripheral blood cells in African children under two years in response to stimulation with NTS was impaired compared with older children and the oxidative burst activity correlated with anti-Salmonella IgG titres. Preopsonising NTS with immune serum overcame this deficit in oxidative burst activity. We found that anti-Salmonella antibody and complement were required for phagocytosis, oxidative burst and blood cell killing of NTS. High levels of IL-6, TNF-a, IFN-y and IL-10 cytokines were secreted by peripheral blood cells following stimulation with NTS, but antibody was not required for this. In children with NTS bacteraemia, titres of antiSalmonella antibodies were increased compared with healthy age-matched individuals. These antibodies were not bactericidal or protective against further episodes of NTS bacteraemia some children. Using our antibody assay as the basis of a potential diagnostic tool for NTS bacteraemia, the sensitivity was low using sera from the acute phase of infection (around 50%) and higher using convalescent sera (greater than 80%). Conclusion: Anti-Salmonella antibody together with complement are required for both cellindependent and phagocyte cell-dependent killing of NTS in peripheral blood of Africans, the latter modality of immunity involving phagocytosis and oxidative burst function. Specific antibody is not a clear requirement for cytokine production in response to NTS.Protective anti-Salmonella antibody develops naturally with age in healthy Africans and high titres of antibody are produced in response to NTS bacteraemia, but are not always protective. The low sensitivity found when using our antibody assay for diagnosis of NTS bacteraemia during acute illness requires further work to establish whether this can be used as the basis of a rapid diagnostic test for this condition. Our findings indicate that a vaccine against NTS for Africa should induce production of protective bactericidal and opsonic antibodies in young African children.