Two types of mooring systems, which have the similar static restoring stiffness, are employed in a semi-submersible platform, respectively. The mooring lines consist of chain-wire-chain and chain-polyester-chain. Firstly, the coupled numerical model between the semi-submersible platform and its mooring system are built. The sea states in South China S4 area are conducted as the ocean environmental loads, and the time series of mooring tension are calculated. Then, the rain flow counting method is employed to obtain the fatigue load spectrum in each short-term sea state. Finally, The Miner linear cumulative law model is used to calculate the fatigue damage of the two types of mooring systems in long-term sea state.