Understanding the biological basis of clinical risk factors for severe COVID-19 is required to ensure at-risk patient populations receive appropriate clinical care. Patients with decompensated liver cirrhosis, in particular those classified as Childs-Pugh class B and C, are at increased risk of severe COVID-19 upon infection with SARS-CoV-2. The biological mechanisms underlying this are unknown. We hypothesised this may be due to changes in expression levels of intrinsic antiviral proteins within the serum as well as alterations in the innate immune response to SARS-CoV-2 infection. We identified significant alterations in the serum proteome of patients with more severe liver disease and an increased frequency of auto-antibodies capable of neutralising type I interferons. No difference in SARS-CoV-2 pseudoparticle infection or live SARS-CoV-2 virus infection was observed with serum from decompensated cirrhotic patients. Principal component analysis of the serum proteome identified two main clinical parameters associated with serum proteome changes – aetiology and MELD-Na score. Among patients with MELD-Na scores >20 we detected significant inhibition of IFN-α2b and IFN-α8 signalling but not IFN-β1a, mediated by auto-antibodies. Our results suggest pre-existing neutralising auto-antibodies targeting type I IFN may increase the likelihood of severe COVID-19 in chronic liver disease patients upon SARS-CoV-2 infection and may also be of relevance to other viral infections in this patient population.