Purpose: Treatment for vesicoureteral reflux remains controversial. Lacking an evidence-based treatment protocol, we offered the option of terminating prophylactic antibiotics in otherwise healthy patients with persistent vesicoureteral reflux at age 5 years or greater. We report outcomes with respect to the urinary tract infection incidence and to whether surgical intervention was eventually done. Materials and Methods: We obtained institutional review board approval to retrospectively review the records of all children with vesicoureteral reflux from December 1999 to February 2009. Of this group we selected children 5 years old or older who had been taken off prophylactic antibiotics. We assessed children with primary vesicoureteral reflux in detail. Results: The records of 1,217 that we reviewed showed that antibiotics were discontinued in 185 patients, including 160 girls (89%) and 25 boys (11%), at an average age of 6.2 years. Average followup was 2.0 years with recorded followup up to 8 years off prophylaxis. In 50 girls (91%) and 5 boys (9%), urinary tract infection developed after discontinuing prophylaxis. Correction was done in 57 patients, including open repair in 34 and endoscopic injection in 23. Two patients underwent intervention at parent request after an average of 0.7 years of uneventful observation. We identified no parameter predicting patients at risk for urinary tract infection. Conclusions: Urinary tract infection develops in 29% of patients 5 years old or older with persistent vesicoureteral reflux within 2 years after the cessation of prophylaxis. Most of these cases are febrile. Discontinuing antibiotics is reasonable but a prospective, randomized, long-term, multi-institutional trial is required to determine whether this approach is beneficial. © 2010 American Urological Association Education and Research, Inc.