Purpose Factors that have a role in endopyelotomy failure have not been fully elucidated but are believed to include high grade hydronephrosis and the presence of crossing vessels at the ureteropelvic junction. Materials and Methods We retrospectively analyzed the importance of renal function, hydronephrosis, ureteral stents, surgeon experience and crossing vessels in determining the outcome of endopyelotomy. Results Of 401 percutaneous antegrade endopyelotomies performed at our medical center during the last 12 years 60 failed and 54 of these patients underwent surgical exploration. Patients with high grade hydronephrosis and poor initial renal function were much less likely to have successful endopyelotomy than those with moderate hydronephrosis or good renal function (success rates 50 versus 96 and 54 versus 92%, respectively, p <0.001). The most common findings at exploration included severe extrinsic fibrosis and intrinsic fibrotic stenosis. Obstructing crossing vessels were present in 13 patients explored, suggesting a possible role in causing failure in only 4% of all endopyelotomy patients. Conclusions Patients with high grade hydronephrosis and poor initial renal function are much more likely to experience endopyelotomy failure. Crossing vessels appear to have a less significant role in endopyelotomy failure than has been previously suggested.