Abstract Introduction Recent clinical observational studies claimed that long term use of proton pump inhibitors (PPIs) might lead to kidney injury that might progress to end-stage renal disease. Aim of the work Was to verify these claims by an in vivo experimental study in the rat. Materials &methods Fourty two adult male albino rats were assigned in four groups Control group (I) in which rats were not administrated any treatment . In groups IIa, IIb, IIc rats received daily oral omeprazole in dose of 0.75mg per kg. for 2,4,or 6 weeks successively. At the end of experiment, blood samples were collected for serum creatinine and blood urea nitrogen (BUN) measurement. Then animals were sacrificed and kidney specimens were processed into paraffin blocks, sectioned and stained with H&E, Mallory trichrome &PAS. Stained sections and image analysis were used to count vacuolated cells, pyknotic nuclei, tubular casts and area precent of collagen fiber deposition then data was subjected to statistical analysis. Results Histological examination of renal sections from omeprazole treated group showed sectional kidney injury in renal corpuscle, renal tubules and sever vascular congestion with inflammatory cell infiltrate in renal interstitium . Thickening of basement membrane was seen by PAS, while progressive increase in collagen fiber deposition was detected by Mallory trichrome stain . Morphometry, image analysis statistical analysis confirmed histological findings. Statistical significant increase in number of vacuolated cells, pyknotic nuclei, hyaline casts and area percent of collagen fiber deposition compared with control group. Clear deterioration of renal function tests was observed across the 3 time points of the study compared with the control with highly significant rise of serum creatinine in 4 & 6 weeks group compared with the control. Results of the study were time -dependent with the worst damage in the 6 week group (IV). Conclusion The present study declared that long term use of omeprazole resulted in structural damage of rat renal tissue with associated deterioration of renal function in a time dependent manner. Extreme caution should be taken with clinical prescription of omeprazole and close monitoring of renal function is highly recommended.