AIM: To evaluate the effects of liposomal bupivacaine for interscalene brachial plexus block on postoperative analgesia and diaphragmatic function in patients undergoing arthroscopic rotator cuff repair surgery based on a  randomized controlled trial. METHODS: Forty patients who scheduled to undergo arthroscopic rotator cuff repair surgery, regardless of gender, aged 18 to 65 years, ASA grade I or II were selected from October 2023 to February 2024. The patients were randomly divided into bupivacaine liposome group (group LB) and the levobupivacaine group (group BV), with 20 cases in each group. Patients in both groups received an ultrasound-guided interscalene brachial plexus block, 15 mL mixed liquids (bupivacaine liposome 10 mL+0.5% levobupivacaine 10 mL) were injected into the level of C5-C6 nerve roots and 5 mL onto the surface of prevertebral fascia in the LB group, and same volume of 0.375% levobupivacaine were injected at the same sites in the BV group respectively. Standardized general anesthesia and standardized postoperative analgesia were followed. The primary outcome measures included 48 h rest/motor numerical rating scale (NRS) scores after surgery and the incidence of hemidiaphragmatic paralysis (HDP) after block. The secondary outcome measures included rest/motor NRS scores at other time points after surgery, pulse oxygen saturation (SpO2) 30 min after block, duration of sensory and motor block, number of analgesic pump presses, time of first postoperative used of opioid drugs and opioid consumption, use of additional analgesics in the wards, satisfaction with analgesia, and the occurrence of perioperative adverse effects and neurological complications. RESULTS: Compared with group BV, patients in LB group showed lower rest NRS scores at 48 h postoperation (P<0.05) and higher incidence of HDP at 24 h after block (45% vs. 5.3%, P<0.05). However, there was no significant difference in motor NRS scores at 48 h, HDP incidence at 30 min and 6 h after block between the two groups (P>0.05). Both groups showed a decrease in SpO2 after block compared to before block (P<0.05). Compared with BV group, patients in LB group had a significantly longer duration of sensory and motor block (P<0.01), fewer effective presses with the analgesic pump (P<0.01), delay in first opioid use and less opioid consumption (P<0.05), higher level of satisfaction with analgesia (P<0.01), and a lower rate of use of additional analgesics in the ward (P<0.05). There was no statistically significant difference in the total intraoperative remifentanil consumption, incidence of perioperative adverse reactions and neurological complication between the two groups (P>0.05). CONCLUSION: Compared with using levobupivacaine alone, the addition of liposomal bupivacaine for interscalene brachial plexus block in arthroscopic rotator cuff repair can reduce postoperative NRS scores, decrease postoperative opioid dosage and significantly prolong blockduration, but can easily lead to longer duration of HDP in patients.