Introduction: Warfarin is an oral anticoagulant that requires ongoing monitoring with time in therapeutic range (TTR), a common measure of the quality of warfarin control and likelihood of adverse events including bleeds. Numerous factors can influence these warfarin outcomes including drug interactions. Proton pump inhibitors (PPIs) have been reported to interact with warfarin but there remain conflicting reports with regard to the impact on bleeds and limited data on TTR. Therefore, the aim of this study was to determine the effect of PPIs on warfarin control using TTR and bleeds as endpoints. Methods: Retrospective data were collected for patients managed by a warfarin management clinic in Queensland. Data collected included current medications, reported bleeds and INR results to calculate TTR. Patients were grouped as taking PPIs or not taking PPIs. Analysis of TTR and bleeds occurred for these groups both before and after exclusions of other medication reported to interact with warfarin. Results: Of the 4494 included patients, almost half (44.5%) were taking PPIs with esomeprazole most commonly (34.8%) prescribed. Patients taking PPIs had significantly reduced TTR compared with patients not taking PPIs both before (78.5 ± 9.7% vs 81.7 ± 10.2%, P < 0.0001) and after (84.4 ± 5.1% vs 89.4 ± 8.0%, P < 0.0001) excluding all other interacting medications with warfarin. Patients taking PPIs also had significantly higher incidence of minor bleeds compared with patients not taking PPIs (32.4% vs 26.1%, P = 0.0487). Discussion: Patients taking PPIs with warfarin had significantly lower TTRs and higher incidence of minor bleeds. This combination warrants additional caution and monitoring with warfarin control as measured by TTR potentially affected.