Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANGII-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANGII levels in urine. After 14 days of ANGII infusion (400ng/kg/min), the increases in systolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and ENaC, as well as lower ANGII and renin content in urine compared to WT. In isolated CD from CDPRR-KO mice, patch clamp studies demonstrated that ANGII-dependent stimulation of ENaC activity was reduced due to fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANGII infusion by enhancing renin activity, increasing ANGII, and activating ENaC in the distal nephron segments.