Background: To compare the treatment outcomes between percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for the management of stones larger than 2 cm in patients with solitary kidney. Methods: One hundred sixteen patients with a solitary kidney who underwent RIRS (n = 56) or PCNL (n = 60) for large renal stones (>2 cm) between Jan 2010 and Nov 2015 have been considered. The patients' characteristics, stone characteristics, operative time, incidence of complications, hospital stay, and stone-free rates (SFR) have been evaluated. Results: SFRs after one session were 19.6% and 35.7% for RIRS and PCNL respectively (p = 0.047), but the SFR at 3 months follow-up comparable in both groups (82.1% vs. 88.3%, p = 0.346). The calculated mean operative time for RIRS was longer (p < 0.001), but the mean postoperatively hospital stay was statistically significantly shorter (p < 0.001) and average drop in hemoglobin level was less (p = 0.040). PCNL showed a higher complication rate, although this difference was not statistically significant. Conclusions: Satisfactory stone clearance can be achieved with multi-session RIRS in the treatment of renal stones larger than 2 cm in patients with solitary kidney. RIRS can be considered as an alternative to PCNL in selected cases.