Ureteroceles associated with the upper pole of a complete ureteral duplication are known as duplex system ureteroceles (DSUs). A limited knowledge of the natural history of this condition makes its management in neonates and infants controversial. Asymptomatic neonates diagnosed antenatally in the absence of severe hydroureteronephrosis (HUN) are at low risk of developing urinary tract infections during the first months of life. These patients might, therefore, begin antibiotic prophylaxis and undergo comprehensive assessment by 3-6 months. Subsequently, conservative management can be viable in patients without severe HUN or high-grade vesicoureteral reflux (VUR). Cases of DSUs with severe HUN but no VUR can be treated by an upper urinary tract approach or by endoscopic decompression depending on upper pole function. Patients with preoperative VUR represent the most challenging cases. If VUR cure is considered necessary, lower urinary tract reconstruction is recommended. Endoscopic decompression allows for a definitive treatment in at least 50% of cases and, in the remaining cases, can be combined with conservative management or endoscopic treatment of VUR. Nonfunctioning or poorly functioning upper poles can be left in situ both in lower urinary tract reconstruction and after endoscopic decompression. Parental preferences should also be taken into account in the decision-making process.