Introduction: In France, a heat warning system (HWS) has been implemented almost two decades ago and rely on some official heat wave (HW) definitions. However, no study has compared the burden associated with a large set of alternative HW definitions to the official definitions. Such comparison could be particularly helpful to identify HW conditions for which effective HWS would minimize the health burden across various geographical contexts and possibly update thresholds to trigger HWS. The aim of this study is to identify (and rank) definitions that drive the highest health burden in terms of mortality to inform future HWS across multiple cities in France. Methods: Based on weather data for 16 French cities, we compared the two official definitions used in France to: i) the Excess Heat Factor (EHF) used in Australia, and ii) 18 alternative hypothetical HW definitions based on various combinations of temperature metrics, intensity, and duration. Propensity score matching and Poisson regressions were used to estimate the effect of each HW exposure on non-accidental mortality for the May-September period from 2000 to 2015. Results: The associations between HW and mortality differed greatly depending on the definition. The greatest burden of heat was 1,055 (95% confidence interval "CI": [856; 1,302]) deaths per summer and was obtained with the EHF. The EHF identified HW with 2.46 (95% CI: [1.92; 3.58]) or 8.18 (95% CI: [6.63; 10.61]) times the global burden at the national level obtained with the climatological indicator of the French national weather service and the HW indicator of the French national HWS, respectively and was the most impactful definition pattern for both temperate oceanic and Mediterranean climate types. Conclusion: Identifying the set of extreme heat conditions that drive the highest health burden in a given geographical context is particularly helpful when designing or updating heat early warning systems.