Bacterial infection is frequently diagnosed in cirrhotic patients with variceal hemorrhage. The aim of this study was to assess the incidence of failure to control bleeding in cirrhotic patients during the first 5 days after the episode of variceal bleeding in relation to the diagnosis of bacterial infection and use of antibiotics. One hundred seventy-seven consecutive admissions for gastrointestinal bleeding in 151 patients were evaluated prospectively. From them, 163 admissions for variceal bleeding in 137 patients were included in the main analysis. Bleeding was managed in a standardized protocol using octreotide or terlipressin with sclerotherapy or band ligation for active bleeding at endoscopy. The end points were defined as in Baveno guidelines related to transfusion requirement or fresh hematemesis after 6 hours from time zero. The standardized screening protocol for bacterial infection consisted of chest radiograph and blood, urine, and ascitic fluid cultures. Active bleeding was reported at endoscopy in 86 admissions (53%). Failure to control bleeding occurred in 76 patient admissions (47%). Empirical antibiotic treatment was used in 113 admissions (69%), whereas in 81% of them (91 admissions, 56%) 102 bacterial infections were documented. Multivariate analysis showed that proven bacterial infection (P < .0001) or antibiotic use (P < .003) as well as active bleeding at endoscopy (P < .001) and Child-Pugh score (P < .02) were independent prognostic factors of failure to control bleeding. The results remained unchanged when all patient admissions with gastrointestinal bleeding of any source were included in the multivariate analysis. Bacterial infection is associated with failure to control variceal bleeding and needs to be evaluated in the planning and analysis of clinical trials.