Abstracts The nuclear desalination based on the high temperature gas-cooled reactor (HTGR) with gas turbomachinery and multi-effect distillation (MED) is attracting attention because the coupling system can utilize the waste heat of the nuclear power system for the MED desalination system. In previous work, KAIST proposed the new HTGR + MED coupling scheme, evaluated desalination performance, and performed cost analysis for the system. In this paper, in order to confirm the safety and the performance of the coupling system, we performed the transient analysis with GAMMA-T (GAs Multidimensional Multicomponent mixture Analysis–Turbomachinery) code for the KAIST HTGR + MED systems. The experimental benchmarks of GAMMA-T code were set up before the transient analysis for several accident scenarios. The GAMMA-T code was well validated against steady state and transient scenarios of the He–Water test loop such as changes in water mass flow rate and water inlet temperatures. Then, for transient analysis, the GTHTR300 was chosen as a reference plant. The GTHTR300 + MED systems were made, based on the KAIST HTGR + MED coupling scheme. Transient analysis was performed for three kinds of accidents scenarios: (1) loss of heat rejection through MED plant, (2) loss of heat rejection through heat sink, and (3) overcooling due to abnormal cold temperature of seawater. In all kinds of accident scenarios, maximum peak fuel temperatures were well below than the fuel failure criterion, 1600 °C and the GTHTR300 + MED system could be operated continuously and safely. Specially, in the loss of heat rejection through MED plants, which is related with the failure of the MED plant, the performance reduction was negligible because the reactor thermal power and the generator power decreased by only 1% and 2%, respectively. As the KAIST coupling scheme uses the double stage precooler, it turns out to have lower potential of total loss of heat rejection accidents than the single purpose nuclear power system using a single stage precooler.