Abstract Background The value of band ligation for prevention of the first episode of variceal bleeding has not been fully evaluated. This study compared the efficacy and safety of band ligation vs. treatment with a beta-blocker for the prophylactic prevention of first bleeding in patients with cirrhosis and high-risk esophageal varices. Methods A total of 100 patients with cirrhosis and endoscopically determined high-risk esophageal varices but no history of bleeding were randomized to band ligation (50 patients) or treatment with nadolol (50 patients). In the ligation group, two to 4 elastic bands were deployed during each session. Ligation was repeated at intervals of 3 to 4 weeks until variceal obliteration was achieved. In the nadolol group, the dose of the drug, administered once daily, was sufficient to reduce the pulse rate by 25%. Results In the ligation group, variceal obliteration was achieved in 41 patients (82%), at a mean of 2.7 (1.1) ligation sessions. In the nadolol group, the mean daily dose of nadolol administered was 60 (20) mg. During follow-up (median approximately 22 months), 10 patients (20%) in the ligation group and 16 (32%) in the nadolol group had upper-GI bleeding ( p = 0.23). Esophageal variceal bleeding occurred in 5 patients (10%) in the ligation group and 9 (18%) in the nadolol group ( p = 0.31). By multivariate Cox analysis, Child-Pugh class was the only factor predictive of variceal bleeding. Minor complications were noted in 9 patients (18%) in the ligation group and 4 (8%) in the nadolol group ( p = 0.35). No serious complication was encountered. Twelve patients in the ligation group and 11 in the nadolol group died ( p = 0.62). One patient in the ligation group and 3 in the nadolol group died from uncontrollable variceal hemorrhage. Conclusions Variceal ligation is as effective and as safe as treatment with nadolol for prevention of first variceal bleeding in patients with cirrhosis.