In this paper, we aimed to highlight functional and safety outcomes of highly-comorbid patients undergoing transperineal laser ablation (TPLA) of prostate at a referral academic center. Patients undergoing TPLA from April 2021 and February 2023 with moderate to severe lower urinary tract symptoms (LUTS), prostate volume ranging from 30 to 100 mL, and an American Society of Anesthesiologists (ASA) Score ≥3 were included. All patients were evaluated as unfit for standard surgery. Procedures were performed in an outpatient setting using local anesthesia. Failure after the procedure was defined as the shift to other ultra-minimally invasive surgical treatment or the need for long-term indwelling catheter replacement. Overall, 23 patients were enrolled with a median age of 76 years. Median ASA Score and Charlson Comorbidity Index were 3 and 5, respectively. Of these, 11 (48%) were under antiplatelets, 4 (17%) under new oral anticoagulants (NOACs) and 3 (13%) under warfarin. Six (26%) patients had an indwelling catheter preoperatively. Median prostate volume was 42 mL. Median follow-up was 12 months. No Clavien-Dindo Grade ≥2 complications were recorded. Four/six (66%) patients with an indwelling catheter before TPLA achieved spontaneous micturition. Treatment failure occurred in 2 (8.5%) patients. Of the remaining 21 patients, 12/21 (57%) patients reported an improvement in International Prostate Symptoms Score (IPSS) symptoms class (i.e., severe to moderate, moderate to mild, etc.); all patients whose IPSS symptoms class remained stable (N.=8 [38%]) had a significant improvement of the IPSS score as compared to the preoperative period, while 1 (4.5%) patient reported worsening of LUTS. In conclusion, TPLA appears to be a safe and feasible ultra-minimally-invasive option for LUTS due to benign prostatic obstruction (BPO) in patients with significant comorbidities at high-risk for standard surgical options.