Mooring systems for floating wave energy converters (WECs) must be designed to survive the cyclical loads and motions to which they are subjected as a result of the wave load–WEC interaction and the motions of the WEC in the random elevation of the sea surface. The current study compares simulation procedures for the fatigue analysis of WEC moorings. The objective is to suggest a simulation procedure suitable for an extensive study of the behaviour of WEC systems and thus for the fatigue analysis of mooring lines. A cylindrical, floating WEC with four spread mooring lines is chosen as case study. The dynamics of the WEC system are simulated and analysed using both coupled and de-coupled models in the time-domain. Four types of simulation procedures are compared using commercial software, DNV DeepC, and an in-house solver, MooDy. A systematic fatigue response analysis based on variations of the numerical and physical parameters is conducted. The results are compared with respect to the fatigue damage calculated using the stress-based approach and the rainflow counting method. The simulation procedure using a coupled model is suggested as the preferred numerical method for capturing the interaction between the components of WEC system, which is proven to be crucial for the fatigue damage evaluation of mooring lines.