Proton pump inhibitors are the most commonly used drugs for the treatment of acid peptic disorder, GERD, NSAID induced mucosal injury Z.E.syndrome and for H.pylori infection. They have been recommended to limit the extension of malignancy and reduce chemoresistance due to their property of inhibiting V- ATPases. PPIs inhibit V-ATPase and promote amyloid beta peptide formation which results in to Alzheimer disease. Infertility rate due to male counterpart is increasing. Epididymal luminal acidic pH is essential for keeping sperms in quiescence during their storage and maturation to prevent their premature entry and activation in to seminal vescicles which leads to sperm dysfunction. Specific subunits of V-ATPases present in clear cells of cauda epididymis play a crucial role in luminal acidification. These subunits are B,a4,A and E2 which are highly expressed in the clear cells of human epididymis whose inhibition by drugs like PPIs can result in to male infertility. Acrosomal membrane of sperm possess E1 and a2 isoforms of V-ATPase which are essential of intra acrosomal acidic pH necessary for processing protease zymogen needed for sperm penetration and fertilization of ovum. Their inhibition by PPI can also lead to male infertility. Long term use of PPIs is known to reduce Vit B 12 absorption which in turn affects sperm function. Many studies have observed positive effect of Vit B 12 supplementation on sperm count, morphology, maturity, motility and their DNA. It reduces reactive oxygen species in the sperms and prevent their malfunction. Vit B 12 deficiency results in to hyper homocysteinemia reduces no generation and sperm function. Thus long term use of PPIs can lead to male infertility.