Objective To investigate the clinical efficacy and safety of balloon compression-assisted endoscopic injection sclerotherapy (bc-EIS) for esophageal varices in patients with cirrhosis. Methods From December 2020 to April 2021, cirrhotic patients with esophageal varices who planned to receive endoscopic treatment in the Department of Gastroenterology of the First Affiliated Hospital of Anhui Medical University were selected and randomly divided into the trial group (treated with bc-EIS) and the control group [treated with endoscopic variceal ligation (EVL)] through computer randomization. The varices eradication rate, rebleeding rate and postoperative adverse reactions in the two groups were studied. Results During the study, 93 cases were initially included according to inclusion criteria, among which 9 cases were excluded by exclusion criteria. Finally, 84 cases were included for data analysis, with 42 cases in each group. The esophageal varices eradication rate after the first treatment in the trial group was 88.10% (37/42), which was significantly higher than that in the control group [33.33% (14/42)] (χ2=26.40, P<0.001). The esophageal varices eradication rate after 1 to 2 times and 1 to 3 times of treatment in the trial group were both significantly higher than those in the control group [97.62% (41/42) VS 40.48% (17/42), χ2=29.47, P<0.001; 100.00% (42/42) VS 45.24% (19/42), P<0.001]. The maximum follow-up period was 6 months, and none of the patients had rebleeding in the trial group, and the rebleeding rate in the control group was 4.76% (2/42) (P=0.494). The incidence of thoracic and abdominal discomfort, nausea and vomiting, and abdominal distension in the trial group and control group were 26.19% (11/42) and 35.71% (15/42) (χ2=0.51, P=0.474), 2.38% (1/42) and 7.14% (3/42) (χ2=0.26, P=0.608), and 4.76% (2/42) and 11.90% (5/42) (χ2=0.62, P=0.430), respectively. No other adverse events such as infection, dysphagia, perforation, esophageal tracheal fistula, esophageal stenosis, or ectopic embolism occurred in any group. Conclusion Bc-EIS is effective and safe for the treatment of esophageal varices in patients with cirrhosis, with a one-time varices eradication rate of more than 85%, and can be completely eradicated after 1 to 3 times of treatment.