Introduction: Responding to acts of terrorism requires the effective use of public safety and medical response resources. Self-confidence is an important component of an effective response. This report describes the development, implementation, and evaluation of a multidisciplinary, interactive, and simulation-enhanced course to prepare first responders, including public safety and medical response personnel, to acts of terrorism. Hypothesis: An effective simulation-enhanced curriculum for first responders can be developed to increase the confidence of course participants in responding to acts of terrorism. Methods: Key stakeholders from public safety and medical professions reviewed current curricula as well as distilled knowledge and skills needed to respond to chemical, biological, radiation, and explosive devices. The resultant two-day, 16-hour course combines didactic and interactive sessions that put learners in realistic simulations with performance-based assessments. This includes the use of skill-station exercises, tabletop simulation, triage exercises, and four 40-minute scenario simulations. An assessment tool was developed to measure participants' self-confidence before and after the course in performing six global objectives: 1) recognize a potential terrorist incident; 2 and 3) implement personal and public protective measures; 4) decontaminate the area and personnel; 5) provide emergency medical care; and 6) communicate within the incident management system. Results: One hundred nineteen learners participated in the seven courses offered from August 2003 through September 2003. During this period, 113 (95%) completed both the pre- and post-course self-assessments. More than 98% ( n = 111) showed an increase in their confidence after the course (pre = 27.97 ± 7.303 vs. post = 44.00 ± 5.084, p < 0.0001) in performing all global objectives. Conclusion: Didactic and performance sessions were successfully integrated into a two-day course for professionals likely to respond to terrorist acts. State-of-the-art training was integrated with objective assessment of all learners in four terrorism scenarios. Results from the self-assessment questions indicate that course participants are more confident in their abilities to respond to acts of terrorism as a result of their participation in this course. Ongoing research is correlating self-confidence with cognitive and psychomotor performance.