We review the practice of safety benefits analysis for federal transportation regulations in the USA. Using a case-study approach, we explore the linkages between risk assessment and benefits analysis, adding to previous work exploring these linkages for environmental health regulations. Challenges for calculating the benefits of transportation safety regulations arise because safety outcomes, like many noncancer health effects, typically do not have formal risk relationships like dose–response functions established for them. Analysts often rely on engineering or other expert judgments or resort to qualitative discussions to connect a regulatory intervention to its intended outcome. Challenges also arise when regulatory outcomes are intangible or do not have established metrics. Safety outcomes are not always measurable in concrete terms like mortality risk and may include difficult-to-operationalize concepts like “safety culture.” If the outcome is not measurable, then quantifying or monetizing the expected effects of a regulation is not possible, and the ability to conduct robust qualitative discussions also may be limited. Economists evaluating benefits for safety regulations encounter limitations analogous to difficulties found in health regulations. To inform policymaking effectively, economists and safety experts could look to the relationship developed in environmental economics between economists and health scientists.