Abstract The possible application of an inherent safety approach to the prevention of domino accidents was explored. The application of the inherent safety guidewords to the definition of effective actions for the prevention of domino events was analyzed. Due to the constraints originated by the conventional approach to process design, the “limitation of effects” guideword resulted the more effective in the identification of inherent safety actions to avoid domino events. Detailed design criteria for the improvement of layout in the framework of inherent safety were identified and discussed. Simple rules of thumbs were obtained for the preliminary assessment of safety distances and of critical inventories with respect to the escalation of fires and explosions. The results evidenced that the integration of inherent safety criteria with conventional passive or active protections seems a promising route for the prevention of severe domino accidental scenarios in chemical and process plants.