Background: liver test abnormalities have been described in patients with Coronavirus-2019 (COVID-19), and hepatic involvement may correlate with disease severity. With the relaxing of COVID-19 restrictions, seasonal respiratory viruses now circulate alongside SARS-CoV-2. Aims: we aimed to compare patterns of abnormal liver function tests in patients suffering from COVID-19 infection and seasonal respiratory viruses: respiratory syncytial virus (RSV) and influenza (A and B). Methods: a retrospective cohort study was performed including 4140 patients admitted to a tertiary medical center between 2010–2020. Liver test abnormalities were classified as hepatocellular, cholestatic or mixed type. Clinical outcomes were defined as 30-day mortality and mechanical ventilation. Results: liver function abnormalities were mild to moderate in most patients, and mainly cholestatic. Hepatocellular injury was far less frequent but had a strong association with adverse clinical outcome in RSV, COVID-19 and influenza (odds ratio 5.29 (CI 1.2–22), 3.45 (CI 1.7–7), 3.1 (CI 1.7–6), respectively) COVID-19 and influenza patients whose liver functions did not improve or alternatively worsened after 48 h had a significantly higher risk of death or ventilation. Conclusion: liver function test abnormalities are frequent among patients with COVID-19 and seasonal respiratory viruses, and are associated with poor clinical outcome. The late liver tests’ peak had a twofold risk for adverse outcome. Though cholestatic injury was more common, hepatocellular injury had the greatest prognostic significance 48 h after admission. Our study may provide a viral specific auxiliary prognostic tool for clinicians facing patients with a respiratory virus.