The class III PI3‐kinase, mVps34, has been implicated in autophagy and endocytosis, but its physiological role in the renal collecting duct system is unknown. We generated an mVps34 gene‐floxed mouse and crossed it with Hoxb7‐Cre mice to produce collecting duct‐specific mVps34 knockout mice (mVps34cdKO, KO) and used mVps34flox/flox;Hoxb7‐Cre(−)littermates as controls (mVps34Ctrl, Ctrl). By embryonic day 17.5, KO mice began to show dilated collecting ducts and proximal tubules, the earliest morphological alterations observed. At birth, KO mice exhibited markedly decreased kidney‐to‐body weight ratios (0.21±0.02% in KO vs. 0.42±0.18% in Ctrl; N=10, P<0.0001), with indistinguishable body weight. By 4 weeks of age, KO mice had a 48% reduction in glomerular number (N=6, P<0.0008) and exhibited unproportionally thinner renal medulla, marked glomerular and tubular hypertrophy, glomerulosclerosis, interstitial fibrosis, proteinuria, and elevated BUN. By 12 weeks of age, KO mice developed hypertension (129.12±0.5 mmHg vs. Ctrl mice: 110.54±0.01; N=7, P<0.0001). TUNEL‐ and cleaved caspase 3‐positive cells were markedly increased, with decreased Akt phosphorylation. These data demonstrate an essential role for mVps34 in the renal collecting duct dictating nephron number and maintaining normal renal structure and function through a mechanism of antagonizing programmed cell death.