In this paper, a detailed procedure to study the mooring line conditional strength reliability of a semi-submersible platform in a 100-year sea state is presented. A fully coupled analysis is conducted to calculate the mooring line tension of a deepwater semi-submersible floating system operated in the 100-year wave condition in South China Sea. 3-h extreme mooring line tensions are estimated by the average conditional exceedance rate (ACER) method from the data obtained by 10 and 20 min fully coupled dynamic simulations, and the results are validated by the global maximum method. A kriging metamodel is trained to predict the 3-h mooring line extreme tension taking into account the effect of random hydrodynamic drag coefficients. The hydrodynamic sampling points are generated by Latin hypercube sampling technique. A reliability analysis is carried out by Monte Carlo simulation considering the random hydrodynamic drag coefficients and mooring line breaking strength.