Spontaneous bacterial peritonitis (SBP) is associated with risk of acute on chronic liver failure (ACLF). Current guidelines recommend primary and secondary antibiotic prophylaxis for patients with cirrhosis and ascites who are at risk of a first episode and to prevent recurrence, respectively. Factors associated with prophylaxis failure leading to SBP, ACLF, and increased mortality are not well established. Gram-positive and multidrug-resistant organisms have become more frequently associated with SBP, particularly in the setting of ACLF. Efforts to understand how long-term antibiotic therapy may affect individual risk of SBP in this population will be critical to developing optimal preventive strategies.