Background: Proton pump inhibitors (PPIs) are widely used worldwide and have been linked to kidney diseases. However, it remains unclear about the role of PPI use in the development of chronic kidney disease (CKD). Aims: To examine the association between PPI use and risk of CKD. Methods: This is a prospective analysis of 472,373 participants free of any renal failure diagnosis from the UK Biobank. Incident CKD was identified based on medical history and linkage to data on primary care and hospital admissions. Self-reported PPI use was firstly assessed using a touchscreen questionnaire, and then confirmed by a trained staff. We estimated the hazard ratios (HRs) and confidence interval (CIs) with Cox regression models adjusting for potential confounders. The number needed to harm (NNH) was calculated at one and five years of follow-up. Results We documented 7,291 cases of CKD over a median of 8.1 years follow-up. After adjustment for potential confounders, regular PPI users had a 24% increased risk of CKD incident compared to non-regular PPI users (HR1.24, 95%CI1.16 -1.33). The NNH was 773.1 and 177.5 for one and five years of follow-up, respectively. Directly compared with H2 receptor antagonist, a less potent acid suppressor, PPI use was associated with 17% higher risk of CKD (HR 1.17, 95% CI 1.00 to 1.36). Conclusions Regular use of PPI is associated with an increased risk of CKD. Healthcare providers should carefully weigh up the potential benefits against risk in prescribing PPIs, particularly for long-term continuous use.