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Summary Background The risk of having a first cirrhosis-associated variceal bleed is lowered by about 50% by β-blockers. Use of β-blockers is currently recommended for patients with cirrhosis and oesophageal varices that are at risk of bleeding. We aimed to test the effectiveness of isosorbide mononitrate as an adjunct to the β-blocker nadolol in the prophylaxis of first variceal bleeding in these patients. Methods We did a randomised multicentre study to compare the non-selective β -blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 relatively well (Child-Pugh score ≤11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alone received a single oral 40 mg daily dose. Every second day the dose was titrated to achieve 20–25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or severe headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 months. Findings During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadalol plus isosorbide mononitrate group had variceal bleeding (logrank test p=0·03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7·5% in the combined treatment group (95% CI for difference 1–25%). Two patients in each group had a non-variceal bleed related to portal hypertension. 14 patients from the nadolol only group and eight from the combined treatment group died during the study period (log-rank test p=0·09). Four and eight patients, respectively, had to discontinue one of the drugs because of side-effects. Interpretation Nadolol plus isosorbide mononitrate is signifcantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirrhosis, and has few side-effects.