This study leverages the availability of a national comprehen- sive database in an integrated network of health systems to examine the association between PPI exposure and long-term renal outcomes. Among users of acid-suppression therapy, H2 blockers and PPI—2 classes of drugs generally prescribed for similar indications—we have shown that exposure to PPI is associated with increased risk of development of CKD, pro- gression of kidney disease, and risk of ESRD. The results also suggest a graded relationship between duration of exposure and risk of renal outcomes. The results were consistent in multiple sensitivity analyses, including an assessment of risk in a 1:1 propensity score-matched and balanced cohort of H2 blocker and PPI users where risk of renal outcomes was sig- nificantly elevated in patients treated with PPI compared with those treated with H2 blockers, and a 1:1 propensity