BACKGROUND: Severe traumatic brain injury (sTBI) is frequently complicated with acute lung injury (ALI). Galectin3 poses a pivotal role in acute brain injury and non-traumatic ALI. Here, serum galectin3 was quantified with an intent to unravel its prognostic significance and mediation effects of ALI in humans with sTBI. METHODS: Serum galectin3 levels were detected in 295 patients with sTBI and 124 healthy subjects in this prospective cohort study. The Glasgow Coma Scale (GCS) scores and Rotterdam computed tomography (CT) scores were recorded. The extended Glasgow outcome scale (GOSE) scores of 1-4 at six-month mark after sTBI signified a poor prognosis. Results were verified by employing multivariate methods. RESULTS: Patients, relative to controls, exhibited pronouncedly incremental serum galectin3 levels. Serum galectin3 levels were linearly and independently relevant to GCS, Rotterdam CT, GOSE scores, and the likelihoods of ALI and poor prognosis. Serum galectin3 levels negligibly interacted with age, sex, hypertension, diabetes, smoking and alcohol habits in predicting ALI and poor prognosis. Serum galectin3 levels efficaciously discriminated probabilities of ALI and poor prognosis. Within the context of propensity score matching, a worse prognosis was evidently occupied by patients with higher serum galectin3 levels. Serum galectin3 levels, in conjunction with GCS, Rotterdam CT scores and ALI, were consolidated to construct a prognosis model, and along with GCS and Rotterdam CT scores, to configure an ALI model. Both models were visually represented by the monogram, and were operated efficiently in the assessment of various statistical metrics. Moreover, ALI partially mediated association of serum galectin3 levels with poor prognosis. CONCLUSIONS: Elevated serum galectin3 levels after sTBI may be significantly pertinent to trauma intensity, ALI and poor prognosis, and its association with poor prognosis may be in part mediated by ALI, substantializing serum galectin3 as an encouraging prognostic predictor of sTBI.