BACKGROUND: Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches. METHODS: Post hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation. RESULTS: Of 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21-1.95], P < 0.001) and PFS (1.34 [1.12-1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73-1.39], P = 0.969; PFS 0.97 [0.76-1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77-1.36) for PPI users compared to 0.68 (0.54-0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68-1.35]; PPI non-users 0.66 [0.50-0.87]; P [interaction] = 0.095). CONCLUSIONS: PPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.