This study introduced a systematic approach for assessing alternative operational models and to determine optimal values for some of the core design parameters in an RFID sensor tag-based cold chain system. First of all, we defined an RFID and sensor data collection and storage model. Next, we developed an RFID sensor tag-based cold chain simulation model and a simulator based on Discrete Event System Specification (DEVS) formalism. Finally, based on a case study, we demonstrated a procedure for determining the optimal sensing interval value with the proposed simulator. The results from the case study have shown that the proposed approach presents important advantages to analyze the Key Performance Indicator (KPI) of cold chain systems according to changes of RFID sensor tag-based cold chain system's operation models and parameter values. (C) 2012 Elsevier Ltd. All rights reserved.