BACKGROUND: Acute respiratory failure (ARF) is a heterogeneous syndrome in which early differentiation between infection-related and non-infection-related etiologies remains challenging. This study aimed to characterize the inflammatory profile of type I ARF and identify candidate biomarkers associated with the infection-related type I ARF. METHODS: In this prospective observational cohort study, 98 patients with type I ARF and 30 healthy controls were enrolled. The plasma levels of 92 inflammation-related proteins were measured using the Olink Inflammation Panels. Type I ARF-associated biomarkers were first identified by comparing type I ARF patients with healthy controls, followed by the identification of infection-related biomarkers within the type I ARF cohort. False discovery rate correction and random forest-based feature ranking were applied. RESULTS: Compared with non-infection-related type I ARF (NonInf-ARF), infection-related type I ARF (Inf-ARF) was associated with a higher incidence of acute respiratory distress syndrome (ARDS) and greater use of advanced life-support therapies. A comparison with healthy controls identified 64 significantly dysregulated biomarkers, representing the inflammatory features of type I ARF. Twenty of the 64 type I ARF-associated biomarkers remained significantly different between the Inf-ARF and NonInf-ARF groups (q<0.05). Neurotrophin-3 (NT-3), interleukin-18 receptor 1 (IL-18R1), interleukin-18 (IL-18), and C-X-C motif chemokine ligand 10 (CXCL10) consistently ranked among the top features across the different analytical methods. CONCLUSION: NT-3, IL-18R1, IL-18, and CXCL10 were identified as candidate biomarkers associated with the Inf-ARF, which may provide additional information for early etiologic stratification.