Background: The decision for using supine or prone position in percutaneous nephrolithotomy (PCNL) is still debatable. The aim of this study is to compare the efficacy and safety profile of the supine and prone position when performing PCNL. Methods: A systematic electronic search was performed using the database from MEDLINE, Cochrane library and Google Scholar from January 2009 to November 2019. The outcomes assessed were stone free rate, major complication rate, length of hospital stay and mean operation time. Results: A total of 11 articles were included in qualitative and quantitative analysis. The efficacy of PCNL in supine position as determined by stone free rate is significantly lower than in prone position (OR: 0.74; 95% CI: 0.66 – 0.83; p<0.00001), However, major complication rate is also lower in the supine group compared with the prone group (OR: 0.70; 95% CI: 0.51 – 0.96; p=0.03). There is no statistically significant difference in the length of hospital stay and mean operation time between both groups. Conclusion: Prone position leads to a higher stone free rate, but also a higher rate of major complication. Thus, the decision of using which position during PCNL should be based on the surgeon’s experience and clinical aspects of the patients.