Alcohol-associated hepatitis (AH) has a high 30-day mortality in patients with a severe AH (sAH). Corticosteroids (CS) are used for patients with sAH but has limitations. There are no biomarkers measured upon hospitalization that predict steroid responsiveness. Signal regulatory protein alpha (SIRPα) is a receptor that regulates inflammation. The role of SIRPAα has not been studied in patients with AH. In a prospective test and validation cohort of sAH patients treated with CS, plasma cytokines and SIRPα levels were measured. Studies with Sirpa mice and in vitro studies were performed to characterize the impact of Sirpa and cleavage. Plasma SIRPα levels were elevated at baseline in CS-NR vs CS-R in both cohorts. Plasma SIRPα levels were also elevated with disease severity and mortality. CS-NR patients had increased pro-inflammatory cytokines. SIRPα cleavage was induced by EtOH and LPS and associated with ADAM10 activity and pro-inflammatory cytokine release. ADAM10 inhibition reduced SIRPα cleavage and pro-inflammatory cytokine release. Sirpa mice developed exacerbated liver injury and inflammation in an experimental model of ALD. Plasma SIRPα is a potential biomarker to predict response to CS and prognosis. Sirpa mice develop a hyper-inflammatory phenotype similar to SIRPα cleavage in humans. Future clinical studies are necessary to validate plasma SIRPα as a predictive biomarker to guide the use of CS in patients with sAH.