Based on a large body of evidence from 42 trials, we found that PCNL compared with RIRS may improve stone-free rates and may reduce the need for secondary interventions, but probably has little or no effect on major complications. PCNL compared with RIRS may have little or no effect on ureteral stricture rates and may increase length of hospital stay. We found no evidence on unplanned medical visits or participant quality of life. Because of the considerable shortcomings of the included trials, the evidence for most outcomes was of low certainty. Access size for PCNL was less than 24 Fr in most studies that provided this information. We expect the findings of this review to be helpful for shared decision-making about management choices for individuals with renal stones.