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Background: Proton pump inhibitors (PPIs) are associated with acute tubulointerstitial nephritis and there are reports associating their use with the development of chronic kidney disease (CKD)., Aim: To determine if PPI use is associated with major adverse renal events (MARE) in patients with CKD., Design: Observational cohort study comprising patients with CKD attending secondary care renal clinics from 1 January 2006 until 31 December 2016., Methods: We collated baseline clinical, socio-demographic and biochemical data at start of PPI (PPI group) or study inception (control group). MARE was considered a composite of doubling of creatinine or end-stage renal disease. Association between PPI exposure and progression to MARE was assessed by cause-specific hazards competing risk survival analysis., Results: There were 3824 patients with CKD included in the analyses of whom 1195 were prescribed a PPI. The PPI group was younger (64.8 vs. 67.0 years, P < 0.001), with lower estimated glomerular filtration rate (eGFR) (30 vs. 35 ml/min, P < 0.001) and more proteinuria (64 vs. 48 mg/mmol, P < 0.001). PPI use was associated with progression to MARE on multivariable adjustment (hazard ratio 1.13 [95% confidence interval 1.02-1.25], P = 0.021). Other factors significantly associated with progression to MARE were higher systolic blood pressure, lower eGFR, greater proteinuria, congestive cardiac failure and diabetes. Hypomagnesaemia was more common in the PPI group (39.5 vs. 18.9%, P < 0.001)., Conclusion: PPI use was associated with progression to MARE, but not death in patients with CKD after adjusting for factors known to predict declining renal function, including lower eGFR, proteinuria and comorbidities. A prospective cohort study is required to validate these findings., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)