Background Training of emergency procedures is challenging and application is not routine in all health care settings. The debate over simulation as an alternative to live tissue training continues with legislation before Congress to banish live tissue training in the Department of Defense. Little evidence exists to objectify best practice. We sought to evaluate live tissue and simulation-based training practices in 12 life-saving emergency procedures. Methods In the study, 742 subjects were randomized to live tissue or simulation-training. Assessments of self-efficacy, cognitive knowledge, and psychomotor performance were completed pre- and post-training. Affective response to training was assessed through electrodermal activity. Subject matter experts gap analysis of live tissue versus simulation completed the data set. Results Subjects demonstrated pre- to post-training gains in self-efficacy, cognitive knowledge, psychomotor performance, and affective response regardless of training modality (P < .01 each). With the exception of fluid resuscitation in the psychomotor performance domain, no statistically significant differences were observed based on training modality in the overall group. Risk estimates on the least pretest performance subgroup favored simulation in 7 procedures. Affective response was greatest in live tissue training (P < .01) and varied by species and model. Subject matter experts noted significant value in live tissue in 7 procedures. Gap analysis noted shortcomings in all models and synergy between models. Conclusion Although simulation has made significant gains, no single modality can be identified definitively as superior. Wholesale abandonment of live tissue training is not warranted. We maintain that combined live tissue and simulation-based training add value and should be continued. Congressional mandates may accelerate simulation development and improve performance.