The simulation capabilities of RELAP5/MOD3 are analyzed and assessed in comparison with the IIST experiments conducted to investigate the system response to the loss of the residual heat removal (RHR) system during midloop operation. Two IIST experiments are simulated; a one-loop test under closed system conditions and a three-loop test with a vent at the top of the pressurizer. Once the RHR cooling system is lost and if alternate heat sinks are not established in time, the primary system will be heated up by the decay power, causing core boiling, system pressurization, and potential core uncovery and fuel heatup. The predicted responses of system parameters by the current model show reasonable agreement with the experimental data. These key parameters consist of the system pressure transient, temperature histories, and variation in the active heat transfer length within the steam generator. The liquid flooding in the pressurizer and the steam generator can also be captured in the current simulation. A periodic fill-and-down cycle developed in the steam generator U-tubes has been observed in the IIST measured data of oscillatory differential pressure across the steam generator. This phenomenon is not simulated in the calculation. However, the calculated differential pressure will follow the experimental trend and agree qualitatively with the measured data averaged over one fill-and-down cycle. As shown in the comparison of the calculated and experimental data, the overall system responses to the loss-of-RHR system event during midloop operation can be appropriately simulated by the current RELAP5/MOD3 model.