Background: Simulation-based learning is a common educational tool in healthcare training and frequently employs instructional designs based on Experiential Learning Theory (ELT). However, little research explores the effectiveness and efficiency of different instructional design methodologies appropriate for simulations. This study compares two instructional design models, ELT and Guided Experiential Learning (GEL), to determine which is more effective for training the central venous catheterization (CVC) procedure. Methods: Using a quasi-experimental randomized block design, nurse anesthetists completed training under one of the two instructional design models. Performance was assessed using a checklist of CVC performance, pass rates, and critical action errors. Results: Participants in the GEL condition performed significantly better than those in the ELT condition on the overall checklist score after controlling for individual practice time (F[1,29]=4.021, p=0.027; Cohen's d=0.71), had higher pass rates (p=0.006; Cohen's d=1.15), and lower rates of failure due to critical action errors (p=0.38; Cohen's d=0.81). Conclusions: The GEL model of instructional design is significantly more effective than ELT for simulation-based learning of the CVC procedure, yielding large differences in effect size.