BACKGROUND: The e-Lung weighted reticulovascular score (WRVS) is an automated computed tomography biomarker that quantifies interstitial lung disease (ILD) severity and is associated with prognosis in patients with idiopathic pulmonary fibrosis (IPF). The aims of the present study were to evaluate WRVS as a prognostic factor in patients with non-IPF ILD. METHODS: The test cohort comprised patients from the Open Source Imaging Consortium and the validation cohort, patients recruited to the prospective German CoWorker ILD registry. Associations between baseline and serial WRVS with future forced vital capacity (FVC) decline and survival were tested. RESULTS: Median survival was 7.1 and 6.1 years in the test (n=302) and validation (n=378) cohorts, respectively. Baseline WRVS was associated with mortality in test (hazard ratio (HR) 1.11, 95% CI 1.08-1.14; p<0.001, C-index 0.75) and validation (HR 1.12, 95% CI 1.09-1.15; p<0.001, C-index 0.72) cohorts. A threshold WRVS of ≥15% was associated with mortality in both cohorts (HR 4.77, 95% CI 3.11-7.31; p<0.001, C-index 0.71, and HR 3.49, 95% CI 2.48-4.91; p<0.001, C-index 0.63 for test and validation cohorts, respectively). After adjustment for FVC, age and sex, baseline WRVS was associated with future FVC decline or death in test (OR 1.13, 95% CI 1.06-1.21; p<0.001, C-index 0.72) and validation (OR 1.18, 95% CI 1.11-1.25; p<0.001, C-index 0.72) cohorts. A rise in WRVS of 3% on serial computed tomography was associated with mortality in both test (HR 5.69, 95% CI 2.77-11.70; p<0.001, C-index 0.75) and validation cohorts (HR 1.99, 95% CI 1.09-3.65; p=0.026, C-index 0.57). CONCLUSION: In patients with non-IPF ILD, the e-Lung WRVS biomarker is associated with mortality and FVC decline when applied to baseline high-resolution computed tomography scans replicating previous studies in IPF. Patients with an increase in WRVS of 3% on serial computed tomography scans have significantly increased risk of mortality.