Purpose: The aim of this study was to compare the clinical therapeutic effects of flexible ureteroscope lithotripsy (FUL) and percutaneous nephrolithotripsy (PCNL) in the semisupine-lithotomy position for unilateral lower pole calculi with a diameter of 10-20 mm. Patients and methods: A total of 83 patients with unilateral lower pole calculi with a diameter of 10-20 mm were prospectively analyzed from January 2016 to April 2018. A total of 38 cases were treated with PCNL in the semisupine-lithotomy position (PCNL group), while 45 cases were treated with FUL (FUL group). Operative time, hospitalization time, hemoglobin decrease after the operation, success rate of lithotomy, complications, and economical costs were compared between the 2 groups. Results: Treatment was completed successfully in the 2 groups. No serious complications (Clavien III-V) occurred in either group. Stone-free rate of FUL was 88.1%, while that of the PCNL group was 93.8. There were no statistically significant differences (P = 0.07). Operative times and economical costs in the FUL group were significantly higher than those in the PCNL group: (107.8 +/- 28.74) min vs. (67.7 +/- 20.42) min and (14,605 +/- 1,754) yuan vs. (20,142 +/- 2,759) yuan. Hemoglobin decreased after the operation and postoperative hospital stay times were significantly lower than those in the PCNL group: (0.65 +/- 0.39) g/L vs. (6.12 +/- 3.94) g/L and (4.92 +/- 0.68) days versus (6.84 +/- 1.48) days. There were statistically significant differences (P < 0.001). Conclusion: Implementation of PCNL in the semisupine-lithotomy position and FUL for treatment of lower pole renal calculi 10-20 mm is feasible and safe. Success rates of lithotripsy of the two groups are similar. FUL has less trauma and economical costs, with shorter hospitalization times.