In terms of the mooring system of a semi-submersible platform in the South China Sea, the modeling and hydrodynamic calculation of the platform and its mooring system are carried out based on AQWA software. The fatigue reliability of the platform is analyzed by the fatigue reliability calculation principle, and the sensitivity of the mooring line fatigue reliability to the layout, corrosion and wear of the mooring system is mainly studied. The results show that: the fatigue reliability of the mooring line of the semi-submersible platform is higher during the service period; the fatigue reliability of the tensioned mooring system is higher than that of the catenary mooring system; corrosion and wear can cause the continuous reduction of steel chain strength, which will lead to a sharp decline in the fatigue reliability of the mooring line. The analysis results can provide some reference for the fatigue reliability evaluation of the mooring cables of similar semi-submersible platforms.