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Objective. To investigate the risk factors of systemic inflammatory response syndrome (SIRS) induced by flexible ureteroscope combined with Holmium laser lithotripsy. Patients and Methods. The clinical data from 216 consecutive patients who had undergone flexible ureteroscope combined with Holmium laser lithotripsy between August 2015 and May 2019 were retrospectively analyzed. To identify the risk factors of systemic inflammatory response syndrome induced by flexible ureteroscope combined with Holmium laser lithotripsy, the cases were divided into two groups according to whether they developed postoperative SIRS: SIRS group (21 cases) and non-SIRS group (195 cases). Age, gender, body mass index, stone size, surgery time, stone location, hydronephrosis, urine culture, hospital stay, stone-free rate, ureteral access sheath, and diabetes mellitus were collected. Univariate analysis was performed to calculate the potential factors. In order to determine the independence of the various factors, factors that potentially contributed to SIRS were compared between the SIRS group and the non-SIRS group. Furthermore, multivariate logistic regression analysis was used to identify the risk factors of systemic inflammatory response syndrome induced by flexible ureteroscopic lithotripsy. Results. All patients were successfully treated with flexible ureteroscopic lithotripsy. The incidence of SIRS after flexible ureteroscopic lithotripsy was 9.7%. The univariate analysis demonstrated the potential risk factors of systemic inflammatory response syndrome induced by flexible ureteroscopic lithotripsy were stone size (p = 0.002), surgery time (p = 0.01), urine culture (p ≤ 0.001), and ureteral access sheath (p = 0.001). Multivariable logistic regression analysis showed that stone size (p = 0.002 , OR = 1.618 ; 95% CI, 0.452-0.844), surgery time (p ≤ 0.001 , OR = 1.025 ; 95% CI, 1.016-1.034), urine culture (p ≤ 0.001 , OR = 25.795 ; 95% CI, 22.131-30.065), and ureteral access sheath (p ≤ 0.001 , OR = 6.101 ; 95% CI, 5.109-7.284) were independent risk factors for SIRS induced by flexible ureteroscopic lithotripsy. Conclusions. Stone size, surgery time, urine culture, and ureteral access sheath are independent risk factors for SIRS induced by flexible ureteroscopic lithotripsy. Patients with these high-risk factors should be carefully evaluated to reduce systemic inflammatory response syndrome. [ABSTRACT FROM AUTHOR]