Background and aim <p>Shoulder arthroscopy is among the most commonly performed orthopedic procedures. The interscalene brachial plexus (ISB) block is long regarded as the gold standard regional technique for the procedure despite its complications. Ultrasound-guided pericapsular nerve group (PENG) block is now being investigated for shoulder procedures. The present study aimed to compare the clinical outcomes between ultrasound-guided PENG and ISB blocks in the setting of shoulder arthroscopy.</p> Patients and methods <p>The present randomized study was conducted on 50 patients scheduled for elective unilateral shoulder arthroscopy under general anesthesia. They were randomly and equally allocated to one of the study interventions [ISB (<i>n</i> = 25) or PENG (<i>n</i> = 25) blocks] under ultrasound guidance. All outcome assessors were blinded to the allocated interventions.</p> Results <p>No significant differences were noted between the studied groups regarding postoperative heart rate, mean arterial blood pressure and postoperative pain at different assessment intervals. Also, no significant differences were found between the studied groups regarding the frequency of patients requiring pethidine, total 24-h pethidine dose (106.0 ± 30.0 mg versus 94.0 ± 30.0, <i>p</i> = 0.16) and time to first pethidine request (9.1 ± 1.4 h versus 9.7 ± 1.2, <i>p</i> = 0.11). It was noted that PENG block group had significantly lower frequency of phrenic nerve palsy (0% versus 24.0%, <i>p</i> = 0.022) and paresthesia in the arm (12.0% versus 36.0%, <i>p</i> = 0.047).</p> Conclusion <p>The present study concludes that the ultrasound-guided PENG block can provide effective management of postoperative pain following shoulder arthroscopy. Importantly, the PENG block offers this benefit with adequate safety profile.</p> Clinical trial registration <p>The present study protocol was registered at clinicaltrails.gov (Registration number: NCT06235879; Date: February 1, 2024).</p>