Abstract: Objective To analyze the prevalence of viral infections in patients with acute exacerbation of interstitial lung disease (AE-ILD) and their impact on prognosis. Methods A total of 107 patients with AE-ILD, who were admitted to Department of Respiratory and Critical Care Medicine at the Affiliated Hospital of Xuzhou Medical University from March 2021 to June 2023, were selected for this study. Viral detection was performed on blood, sputum, and bronchoalveolar lavage fluid samples using metagenomic next-generation sequencing (mNGS). The prevalence of viral infections and the risk factors affecting patient prognosis were analyzed. Results Among the AE-ILD patients, 88 patients (82.24%) tested positive for viral infections, with the highest detection rate observed for Epstein-Barr virus (EBV), accounting for 56.07% of AE-ILD patients. Statistically significant differences were found between the virus-positive and virus-negative groups in terms of gender, age, procalcitonin (PCT), brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), oxygenation index, intensive care unit (ICU) admission cases, and 90-day mortality (P<0.05). The mortality group was more prone to infection with human herpesvirus 1 (HHV-1, χ²=6.180, P=0.013) and HHV-7 (χ²=8.552, P=0.003) than the survival group. Multivariate regression logistic analysis indicated that infection with HHV-7 (OR: 5.528, 95%CI: 1.335-22.886, P=0.018) and elevated LDH levels (OR: 1.005, 95%CI: 1.000-1.009, P=0.031) were independent risk factors for poor prognosis in AE-ILD patients. Conclusions EBV is the most common type of viral infection in AE-ILD patients. Infection with HHV-7 and high LDH levels are risk factors for poor prognosis in AE-ILD patients.