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Background Malaria presents with unspecific clinical symptoms that frequently overlap with other infectious diseases and is also a risk factor for coinfections, such as non-Typhi Salmonella. Malaria rapid diagnostic tests are sensitive but unable to distinguish between an acute infection requiring treatment and asymptomatic malaria with a concomitant infection. We set out to test whether cytokine profiles could predict disease status and allow the differentiation between malaria and a bacterial bloodstream infection. Methods We created a classification model based on cytokine concentration levels of pediatric inpatients with either Plasmodium falciparum malaria or a bacterial bloodstream infection using the Luminex platform. Candidate markers were preselected using classification and regression trees, and the predictive strength was calculated through random forest modeling. Results Analyses revealed that a combination of 7–15 cytokines exhibited a median disease prediction accuracy of 88% (95th percentile interval, 73%–100%). Haptoglobin, soluble Fas-Ligand, and complement component C2 were the strongest single markers with median prediction accuracies of 82% (with 95th percentile intervals of 71%–94%, 62%–94%, and 62%–94%, respectively). Conclusions Cytokine profiles possess good median disease prediction accuracy and offer new possibilities for the development of innovative point-of-care tests to guide treatment decisions in malaria-endemic regions. [ABSTRACT FROM AUTHOR]