Purpose Despite the widespread application of endoscopic therapy and the debate surrounding the use of prophylactic antibiotics to treat children with vesicoureteral reflux, many pediatric urologists still favor medical management. Breakthrough infection is one of the absolute indications for surgery. Data to predict breakthrough infection are warranted to manage cases of primary reflux. Materials and Methods We reviewed medical records of 72 girls and 138 boys (mean ± SD age at diagnosis 2.66 ± 3.23 years) with primary vesicoureteral reflux who were followed with antibiotic prophylaxis at Aichi Children's Health and Medical Center. We examined multiple factors by univariate/multivariate analysis to elucidate risk factors for breakthrough infection. Results Breakthrough infection developed in 59 children (28%). On univariate analysis higher reflux grade (p <0.05) and abnormal renal scan determined by 99mtechnetium dimercapto-succinic acid (p <0.0001) were significantly associated with breakthrough infection. On multivariate analysis abnormal renal scan was an independent risk factor for breakthrough infection (OR 11.08, 95% CI 0.76–1.72, p <0.0001). Conclusions Abnormal renal scan is an independent risk factor for breakthrough infection. Parents and physicians should remain aware that these patients are at high risk for breakthrough infection, which potentially could lead to renal damage.