Background and Objective: The aim of this study was to compare the efficacy and reliability of holmium (Ho:YAG) laser lithotripsy (HLL) and pneumatic lithotripsy (PL) in percutaneous nephrolithotomy (PCNL) in the treatment of patients with Grade IV kidney stones based on Guy’s Stone Score. Study Design/Materials and Methods: This retrospective study included 103 patients with Grade IV kidney stones out of 440 patients who underwent PCNL through HLL and PL in Second Affiliated Hospital of Shantou University Medical College, China, from January 2016 to December 2018. We analyzed preoperative, intraoperative, and postoperative variables of the patients to evaluate the efficacy and reliability of PCNL procedures. Results: Patients were categorized as Grade I, II, III, and IV, and the patients of each grade were 85 (19.32%), 39 (8.86%), 213 (48.41%), and 103 (23.41%), respectively. In Grade IV, the total operative time (min) for the PL and HLL groups was 137.7 ± 47.79 and 134.27 ± 53.38, respectively (p = 0.744). The variation in laboratory examination values including ΔHGB (g/L), ΔHCT, ΔPCT, and ΔCr (μmol/L) for PL and HLL groups was 19 ± 11.23/12 ± 15.42 (p = 0.012), 0.057 ± 0.034/0.038 ± 0.045 (0.009), 0.027 ± 0.034/0.026 ± 0.034 (0.702), and 3.07 ± 17.4/20.54 ± 65.93 (0.692), respectively. The postoperative hospitalization day was 8.94 ± 4.2 and 7.73 ± 2.75 (p = 0.015), respectively. As for the stone-free rate (SFR), the SFRs for PL and HLL were 48.15% (n = 39/81) and 59.09% (n = 13/22) (p = 0.363), respectively. Conclusions: HLL showed a comparable advantage of not only decreased postoperative hemoglobin and hematocrit but also fewer postoperative hospitalization days. Based on the results of our retrospective study, for those Grade IV kidney stone patients who have a risk of bleeding before PCNL operation, HLL can be a considerable treatment option. Besides, in consideration of reducing human care cost, HLL which showed fewer hospitalization days, would be more welcome by patients.