Purpose: To compare the clinical efficacy and safety in children with vesicoureteral reflux (VUR) of a single injection of two different bulking agents: polydimethylsiloxane (Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux). Methods: A total of 73 patients (106 renal units, 41 boys and 32 girls) aged 2–15 years (mean age, 34.5 months) were included. A single subureteral injection of either Macroplastique or Deflux was performed in 37 children (55 ureters) and 36 children (51 ureters), respectively. VUR was grade II in 34 ureterorenal units, grade III in 23, grade IV in 31, and grade V in 18 ureterorenal units. Results: Overall, the reflux was corrected in 84 of the renal units (86%) with one injection. The correction rates, according to the reflux grade, were 91, 91, 83, and 72% for grades II–V, respectively. At the 3-month follow-up visit, reflux was corrected in 48 (87%) of 55 refluxing ureters in the Macroplastique group and in 43 (84%) of 51 refluxing ureters in the Deflux group. Conclusions: A single subureteral injection of either Macroplastique or Deflux is an effective treatment modality for children with VUR. The procedure was well tolerated, safe, and associated with low morbidity.