Potential link between proton pump inhibitors (PPIs) and hypertension remains unclear. It is uncertain whether such an association exists, whether it represents a class effect, and whether a dose-response relationship is involved.We aimed to investigate the potential class effect associating PPIs with hypertension reporting, and evaluate whether the association follows a dose-dependent pattern.We conducted a disproportionality analysis within VigiBase® to identify signals of hypertension reporting associated with individual PPIs by calculating adjusted reporting odds ratios (aRORs) within a multivariate case/non-case study design. Additionally, we explored the presence of a dose-response relationship. We utilized real-world data from VigiBase®, the World Health Organization (WHO) pharmacovigilance database. We identified that incident hypertension cases using the Medical Dictionary for Regulatory Activities V.26.1 related with at least one PPI administration were systematically collected until October 28th, 2024. Pharmacovigilance signal between PPIs use and hypertension reported and dose dependence between PPIs posology and onset or worsening hypertension were explored.The database contained 26,587 reports of PPI-associated hypertension (2.3%), predominantly among women (63.3%). Hypertension was most frequently reported in the age group of 45-64 years (41.4%). A significant reporting odds ratio (ROR) was observed for almost all PPIs in both univariable (RORs ranging from 1.33 to 1.98) and multivariable analyses (aRORs ranging from 1.15 to 1.31) after adjustments for age group, sex, concurrent antihypertensive medication, and drugs known to induce hypertension, with the exception of lansoprazole (aROR: 0.95). A potential trend suggestive of a dose-response relationship was identified, with doses lower than the median associated with a lower aROR for hypertension compared to doses higher than the median for all PPIs. However, this trend did not reach statistical significance, likely due to insufficient statistical power.This investigation, conducted under real-life conditions, unveils a notable pharmacovigilance safety signal associating PPI usage with hypertension reporting.While a potential dose-response trend was observed, it did not reach statistical significance, possibly due to limited statistical power. Further longitudinal studies are warranted.