Objectives: To develop an evidence base to guide clinicians treating adults with large proximal ureteral stones (LPUS) greater than 10 mm. Methods: A systematic search of PubMed, EMBASE, and Cochrane Library was conducted to identify randomized controlled trials (RCT) concerning different LPUS management techniques including laparoscopic ureterolithotomy (LU), percutaneous nephrolithotomy (PCNL) and ureteroscopic lithotripsy (URL) up until March 2020. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement when searching and determining inclusion. All included articles were quality assessed and the data analyses were conducted with Review Manager (5.3). Results: 12 RCTs involving 1416 patients met our eligibility criteria and were analyzed. Of these participants, 44.6% (n = 632) underwent URL, 25.5% (n = 361) PCNL, and 29.9% (n = 423) LU. Pooled analysis revealed that URL had a significantly lower stone-free rate (SFR) compared to PCNL and LU (both with p < 0.05). URL had a significantly higher ureteral injury rate compared to LU (Relative risk (RR) = 5.27, 95% confidence interval (CI) 1.52 to 18.22, p = 0.009) and PCNL (RR = 4.11, 95% CI 1.03 to 16.34, p = 0.04). However, no significant differences were found between PCNL and LU in terms of SFR or overall complications, both with p > 0.05. URL initially costs less than PCNL (Weighted mean difference (WMD) -597.35US$, 95% CI -823.10 to -371.60, p < 0.00001), but being less effective creates greater demand for repeat or ancillary treatments compared to LU (RR 15.65, 95% CI 2.11-116.12, p = 0.007) and PCNL (RR 8.86; 95% CI 3.19-24.60; p < 0.00001). Conclusions: Both PCNL and LU appear more effective and safer than URL for LPUS; although, LU has higher risk of urine leakage and is more likely incur trauma which requires additional support. However, caution must be taken because this recommendation is based upon a very limited number of clinical studies, and even fewer comparing flexible ureteroscopic technologies. Further prospective real-world studies or RCTs comparing flexible URL, LU and PCNL are required, as well as an in depth analysis of the hidden costs involved in unsuccessful URL treatments.