Purpose To evaluate the safety, efficiency, and size-dependency of the ‘Inverted omega En-bloc (Ʊ)’ holmium laser enucleation of the prostate (HoLEP) in benign prostate hyperplasia (BPH) with lower urinary tract symptoms. Materials and Methods A retrospective analysis of 716 consecutive patients who underwent HoLEP under the care of a single surgeon from 2014–2021. These patients were treated using the ‘Inverted omega En-bloc ’ HoLEP technique for BPH. The patients were divided into 3 groups: Group 1 (<40 mL, n=328), Group 2 (40–60 mL, n=221), and Group 3 (≤60 mL, n=167). Perioperative parameters, safety, and functional outcomes were assessed and analyzed. Results The perioperative parameters, like enucleation time (45.8±26.9 min), morcellation time (13.2±47.5 min), and catheterization duration (1.6±1.2 d) significantly differed to favor smaller prostate sizes (p<0.01). Significant improvements in the IPSS (total, voiding, storage, and quality of life), post-void residual urine, and maximum flow rate were observed 3 months post-HoLEP and continued during the 1-year follow-up period in all groups (p<0.01). The postoperative complications included urethral stricture in 11 patients (1.5%), bladder neck contracture in 12 (1.7%), urinary incontinence in 14 (2.0%), and bladder injuries in 4 (0.6%). Bladder neck contractures occurred only in Group 1. The postoperative surgical management for complications included urethral sounding (n=9, 1.3%), endoscopic internal urethrotomy (n=2, 0.3%), and re-HoLEP for bladder neck contractures in (n=12, 1.7%). The rate of re-HoLEP for regrowing adenomas was 15 (2.1%). Postoperative medications exceeding 6 months were α-blocker (n=22, 3.1%), cholinergics (n=16, 2.2%), anticholinergics (n=58, 8.1%), antidiuretics (n=18, 2.5%), and daily PDE5 inhibitor (n=38, 5.3%). Thirty-four patients (4.7%) had postoperative incidental prostate cancer. Conclusions The inverted omega En-bloc HoLEP technique is safe and effective for the treatment of BPH. Moreover, ‘Inverted omega En-bloc ’ HoLEP is a size-independent and effective method for all prostate sizes.