Background: PPIs are potent inhibitors of gastric acid secretion and can affect the bioavailability of orally administered cancer targeting therapies, such as vascular endothelial growth factor tyrosine-kinase inhibitors (VEGF-TKIs). Smaller preclinical and clinical studies have attempted to assess the interaction between VEGF-TKIs and PPIs in patients with advanced cancers; however, these studies are limited and larger analyses from rigorous datasets have been lacking. We investigate the impact of PPI use on survival in patients with mRCC treated with oral VEGF-TKIs. Methods: A pooled analysis of mRCC patients treated on phase II and III clinical trials was conducted. The primary outcome was to assess overall survival (OS) between PPI users, defined as patients receiving a PPI at baseline, compared to non-PPI users. Secondary outcomes included progression-free survival (PFS), objective response rates (ORR), and adverse events. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: Our cohort consisted of 2,188 patients treated with sunitinib (n = 952), axitinib (n = 626), or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users demonstrated similar OS compared to non-PPI users (median 24.1 vs. 21.3 months, adjusted hazard ratio [aHR] 1.051, 95% confidence interval (CI) 0.769-1.438, p = 0.754). Similarly, PFS (5.5 vs. 8.0 months, aHR 1.016, 95% CI 0.793-1.301, p = 0.902) and ORR (23.3% versus 27.4%, p = 0.344) were not different between PPI users and non-users. These findings were consistent across International mRCC Database Consortium risk groups and by line of therapy. Adverse events were also similar between both groups. Conclusions: In this analysis, we demonstrate that PPI use does not appear to negatively impact the efficacy of VEGF-TKIs in mRCC patients treated in the targeted therapy era. Given the current landscape expanding to include more self-administered treatments, documentation of concomitant medications, and patient education on potential drug interactions are critical for optimizing the utilization of oral cancer targeting therapy.