AbstractImproved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Here, we develop a generalizable host-gene-expression-based classifier for acute bacterial and viral infections. We use training data (N = 1069) from 18 retrospective transcriptomic studies. Using only 29 preselected host mRNAs, we train a neural-network classifier with a bacterial-vs-other area under the receiver-operating characteristic curve (AUROC) 0.92 (95% CI 0.90–0.93) and a viral-vs-other AUROC 0.92 (95% CI 0.90–0.93). We then apply this classifier, inflammatix-bacterial-viral-noninfected-version 1 (IMX-BVN-1), without retraining, to an independent cohort (N = 163). In this cohort, IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.86 (95% CI 0.77–0.93), and viral-vs.-other 0.85 (95% CI 0.76–0.93). In patients enrolled within 36 h of hospital admission (N = 70), IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.92 (95% CI 0.83–0.99), and viral-vs.-other 0.91 (95% CI 0.82–0.98). With further study, IMX-BVN-1 could provide a tool for assessing patients with suspected infection and sepsis at hospital admission.