AIM: This study aimed to develop a simulation activity integrated with an Interactive Response System (IRS) and explore the relative contribution of individual factors influencing participant reaction by applying the National League for Nursing (NLN)/Jeffries Simulation Theory as a study framework. BACKGROUND: Adopting an appropriate theoretical framework to assess the effectiveness of integrating such systems into simulation activity may be beneficial for nursing education innovation. METHODS: A cross-sectional survey was conducted. A four-hour simulation activity was developed for 287 nursing students who completed the designated learning tasks through peer role-play simulation. The role-playing tasks included performing patient assessments, nursing instruction and patient education. Using CloudClassRoom as an IRS, students engaged in real-time questioning, announcements and rating features. Data were collected between March and June 2020. A hierarchical multiple regression model was used to examine the relative importance of individual factors that influenced satisfaction and self-confidence in learning. RESULTS: The findings provide empirical evidence supporting the NLN/Jeffries Simulation Theory, demonstrating that both simulation design and educational practices significantly impact students' self-confidence and satisfaction with learning, accounting for 63.9 % of the variance thereof. Objectives and information, feedback and active learning were significant factors influencing self-confidence and satisfaction. Experience with IRS was identified as making a uniquely significant contribution, providing additional impact beyond that of simulation design and educational practices. CONCLUSIONS: Integrating the NLN/Jeffries Simulation Theory for simulation design with IRS as an interactive platform creates a more effective and engaging learning environment.