Objective To investigate the effect of methylprednisolone (METH) pretreatment on the incidence of urosepsis post percutaneous nephrolithotomy (PCNL) in patients with high-risk factors. Methods Eighty patients who underwent PCNL with high-risk factors of postoperative urosepsis were prospectively selected in this study. They were stratified by gender and randomized into METH or control groups (n=40 in each group). After induction of general anesthesia, 40 mg METH was intravenously administered in METH group before operation, while the equal volume of normal saline was done in the control group. The primary outcome was the incidence of postoperative urosepsis (according to Sepsis 3.0 definition). The secondary outcomes included the incidences of uroseptic shock and system inflammatory response syndrome (SIRS), and the changes of plasma levels of inflammatory markers (C reactive protein[CRP], procalcitonin, tumor necrosis factor α[TNF-α], interleukin[IL]-1β, IL-6, and IL-10) at 2 h and 24 h after operation. Results Six out of 80 patients were excluded. There was no significant difference in the baseline characteristics between the two groups before operation (P>0.05). The incidences of postoperative urosepsis, uroseptic shock and SIRS were 5.4% (2/37), 0 and 18.9% (7/37) in METH group (n=37), and 24.3% (9/37), 10.8% (4/37) and 51.4% (19/37) in the control group (n=37), respectively, with no significant difference in the incidence of uroseptic shock (P>0.05), but with significant differences in the incidences of urinary sepsis and SIRS between the two groups (P<0.05, P<0.01). The plasma level of IL-10 in METH group was higher than that in the control group at 2 h after operation (26.3[149.5] pg/mL vs 5.0[3.6]pg/mL, P<0.01), but lower than that in the control group at 24 h after operation (<5.0[1.5] pg/mL vs 5.9[13.8]pg/mL, P<0.05). The plasma level of IL-6 in the control group was higher than that in METH group at 24 h after operation (34.4[46.5]pg/mL vs 20.7[15.8]pg/mL, P<0.01). No significant difference was found in the levels of other inflammatory markers between the two groups (all P>0.05). Conclusion METH pretreatment can decrease the incidences of urosepsis and SIRS in high-risk patients undergoing PCNL. This protective effect may be attributed to METH pretreatment facilitating the release of IL-10 at the initial stage of inflammatory response, and then inhibiting the subsequent excessive inflammatory response.