This article describes a methodology for a risk-informed benefit–cost analysis that includes (i) risk analysis to quantify risk reduction benefits and (ii) uncertainty analyses to quantify probability distributions over costs and benefits. It also summarizes the lessons from 25 applications of this methodology to evaluate R&D projects of the Science and Technology Directorate of the Department of Homeland Security. The article then illustrates the methodology with a specific application to evaluate the benefits and costs of the Advanced Personal Protection System (APPS), a new garment system developed to protect wildland firefighters. The goals of the APPS project were to reduce risk and to improve comfort. The cost analysis revealed that the APPS garments are more expensive by about $279 per garment system. Total costs were roughly $7.3 million, including the upfront project cost and the increased 5 year cost of purchasing the APPS. Benefits from reduced injuries and fatalities resulted in 5 year benefits of about $19.3 million, with an NPV of $13.6 million in 2019 dollars. In the base case, the benefit–cost ratio was 2.87 and the return on investment was 187 % over 5 years. Taking the perspective of a decision-maker when the project was first funded in 2011, NPVs are $11,993,728, $10,025,519, and $7,967,479 in 2011 dollars for discount rates of 0, 3, and 7 % respectively. An uncertainty analysis of the NPV showed a large variability, ranging from the 5th percentile of $6.4 million to a median of $19.3 million to the 95th percentile of $43.7 million in 2019 dollars. This large range was primarily due to the uncertainty about the reduction of fatality and injury risks and the market penetration rates of the new garments.