Background: Proton pump inhibitors (PPIs) were revealed to regulate gut microbiome alterations and further impact the response to immune checkpoint inhibitors (ICIs). Contradictory impacts on survival were observed in ICI-treated patients when concomitantly use PPI or not. We performed this systematic review and meta-analysis to analyze the association of PPI use with survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases and major oncology conferences proceedings were comprehensively searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI use and PPI non-use in ICI-treated cancer patients were included. Data regarding the characteristics, ICI and PPI treatments and survival outcomes for patients were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effect models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among study results. Results: A total of 20 studies were included, comprising 2812 ICI- and PPI-treated patients and 3990 ICI-treated and PPI-free patients. The pooled HR is 1.30 (95% CI, 1.17-1.45; P<.001) for OS and 1.20 (95% CI, 1.08-1.34; P<.001) for PFS, indicating a significant negative association between PPI use and survival of ICI-treated patients. Subgroup meta-analyses by factors including cancer types, ICI types and time window of PPI use, revealed such associations were in patients with non-small cell lung cancer (OS: HR = 1.40, 95% CI = 1.23 to 1.59, P<.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P<.001) or urothelial cancer (OS: HR = 1.50, 95% CI = 1.26 to 1.80, P<.001; PFS: HR = 1.37, 95% CI = 1.17 to 1.60, P<.001), patients treated with anti-PD-1/PD-L1 (OS: HR = 1.41, 95% CI = 1.30 to 1.53, P<.001; PFS: HR = 1.29, 95% CI = 1.20 to 1.38, P<.001), patients receiving PPI as baseline treatment (OS: HR = 1.43, 95% CI = 1.21 to 1.69, P<.001; PFS: HR = 1.29, 95% CI = 1.16 to 1.44, P<.001) or 60 days before ICI treatment initiation (OS: HR = 1.28, 95% CI = 1.11 to 1.48, P<.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P<.001), rather than concomitantly with ICI initiation. Conclusions: PPIs use in patients treated with ICIs is associated with a shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled, and appear to not impact survival if given temporarily after ICIs initiation. These detailed observations could provide basis for clinical guidelines when concomitantly use PPIs and ICIs.