Purpose Antibiotic prophylaxis is commonly used for medical management of vesicoureteral reflux. Little information exists on compliance with antibiotic prophylaxis in patients with vesicoureteral reflux. Materials and Methods We queried the i3 Innovus (Ingenix®) pharmacy claims 2002 to 2007 database for patients 18 years old or younger with vesicoureteral reflux (ICD-9 code 593.7 plus claim for cystogram) and analyzed those with at least 1 year of followup data. Criteria for management with antibiotic prophylaxis were 2 or more 30-day supplies of antibiotic prescriptions, or 4 or more 14-day supplies of prescriptions if the antibiotic was a penicillin or cephalosporin. Antibiotic prophylaxis compliance was determined using a medication possession ratio, an estimate of the proportion of time that patients have a prescribed drug available for use. Compliance was established as a medication possession ratio of 80% or greater, meaning coverage with antibiotic prophylaxis for 80% of the year or more. Results Of 9,496 patients with vesicoureteral reflux 5,342 (56.3%) were treated with antibiotic prophylaxis. Most patients were female (81%) and 5 years old or younger (79%). Trimethoprims/sulfonamides were most commonly prescribed (62%) and antiseptics were next (24%). Of patients prescribed antibiotic prophylaxis 40% were compliant. Compliance was lower for 6 to 10-year-olds (OR 0.71, 95% CI 0.61–0.83) and 11 to 18-year-olds (OR 0.56, 95% CI 0.41–0.79) compared to younger children (5 years or less). Increased compliance was associated with 1 or more hospitalizations (OR 1.70, 95% CI 1.48–1.97) and 1 or more urologist visits (OR 1.41, 95% CI 1.25–1.58). Conclusions Among patients with vesicoureteral reflux who are prescribed prophylactic antibiotics 40% are compliant with treatment. Young age, frequent hospitalization and specialist visits are associated with compliance. This knowledge may help to develop effective interventions to improve compliance and underscores the importance of reporting compliance in clinical studies evaluating the usefulness of antibiotic prophylaxis in vesicoureteral reflux management.