Objective To evaluate the safety and long-term effectiveness of endoscopic foam sclerotherapy (FS) combined with endoscopic rubber band ligation (ERBL)in the treatment of grade Ⅱ-Ⅲ internal hemorrhoids. Methods Consecutive patients diagnosed as having grade Ⅱ-Ⅲ internal hemorrhoids in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January to December 2020 were prospectively enrolled in the study, and randomly divided into ERBL group and FS combined with ERBL group. The 24 h visual analogue scale (VAS) for pain and 1-week degree of bleeding were evaluated after the treatment. After follow-up of 6 months, the effectiveness of treatment was evaluated. Results A total of 84 patients with age of 54.4±7.9 years were enrolled, 57.1% (48/84) males, and 73.8% (62/84)grade Ⅱ internal hemorrhoids. Forty-three patients were assigned to the ERBL group and 41 to the FS combined with ERBL group. There was no significant difference between the two groups in baseline data (P>0.05). In the FS combined with ERBL group, the mean amount of polidocanol foam was 13.8±2.5 mL, the mean number of injection site was 4.7±1.2, and the median scores of VAS was 0 (0, 3), which was significantly lower than that of ERBL group [2 (0, 4), Z=-2.116, P=0.034]. The bleeding rate 1 week after treatment in the ERBL and FS combined with ERBL group were 20.9% (9/43) and 29.3% (12/41), respectively, and mild bleeding was the main symptom. There was no significant difference between the two groups in the bleeding degree (U=807.0, P=0.378). After 6 months of follow-up, the total effective rates in the ERBL group and the FS combined with ERBL group were 81.4% (35/43) and 90.2% (37/41), respectively （U=684.5, P=0.044）. Conclusion FS combined with ERBL can effectively relieve post-treatment perianal pain, and improve the long-term effectiveness.