The International Alliance of Urolithiasis (IAU) would like to release the latest guideline on percutaneous nephrolithotomy (PCNL) and to provide a clinical framework for surgeons performing PCNL. These recommendations were collected and appraised from a systematic review and assessment of the literature covering all aspects of PCNLs from the PubMed database between January 1, 1976, and July 31, 2021. Each generated recommendation was graded using a modified GRADE methodology. The quality of the evidence was graded using a classification system modified from the Oxford Center for Evidence-Based Medicine Levels of Evidence. Forty-seven recommendations were summarized and graded, which covered the following issues, indications and contraindications, stone complexity evaluation, preoperative imaging, antibiotic strategy, management of antithrombotic therapy, anesthesia, position, puncture, tracts, dilation, lithotripsy, intraoperative evaluation of residual stones, exit strategy, postoperative imaging and stone-free status evaluation, complications. The present guideline on PCNL was the first in the IAU series of urolithiasis management guidelines. The recommendations, tips and tricks across the PCNL procedures would provide adequate guidance for urologists performing PCNLs to ensure safety and efficiency in PCNLs.