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Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF., Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias., Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis., Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)