Abstract Background Interscalene brachial plexus block, the pain relief standard for shoulder surgery, is an invasive technique associated with important complications. The subomohyoid anterior suprascapular block is a potential alternative, but evidence of its comparative analgesic effect is sparse. The authors tested the hypothesis that anterior suprascapular block is noninferior to interscalene block for improving pain control after shoulder surgery. As a secondary objective, the authors evaluated the success of superior trunk (C5–C6 dermatomes) block with suprascapular block. Methods In this multicenter double-blind noninferiority randomized trial, 140 patients undergoing shoulder surgery were randomized to either interscalene or anterior suprascapular block with 15 ml of ropivacaine 0.5% and epinephrine. The primary outcome was area under the curve of postoperative visual analog scale pain scores during the first 24 h postoperatively. The 90% CI for the difference (interscalene-suprascapular) was compared against a –4.4-U noninferiority margin. Secondary outcomes included presence of superior trunk blockade, pain scores at individual time points, opioid consumption, time to first analgesic request, opioid-related side-effects, and quality of recovery. Results A total of 136 patients were included in the analysis. The mean difference (90% CI) in area under the curve of pain scores for the (interscalene-suprascapular) comparison was –0.3 U (–0.8 to 0.12), exceeding the noninferiority margin of –4.4 U and demonstrating noninferiority of suprascapular block. The risk ratio (95% CI) of combined superior trunk (C5–C6 dermatomes) blockade was 0.98 (0.92 to 1.01), excluding any meaningful difference in superior trunk block success rates between the two groups. When differences in other analgesic outcomes existed, they were not clinically important. Conclusions The suprascapular block was noninferior to interscalene block with respect to improvement of postoperative pain control, and also for blockade of the superior trunk. These findings suggest that the suprascapular block consistently blocks the superior trunk and qualify it as an effective interscalene block alternative. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New