Reducing the levelised cost of energy is crucial to accelerating the energy transition. To develop offshore wind solutions in greater water depths, a floating solution is required. The time-domain simulations of these Floating Offshore Wind Turbines (FOWTs) under wind-wave misalignment used in research and industry projects are computationally intensive and limits researchers and industry in their developments. To better understand the sensitivities of the fatigue loads of FOWTs to different parameters and environmental conditions, a computationally efficient method is needed. The aim of this research is to develop a frequency-domain method to quantify the effects of misaligned wind and waves on the response of a semi-submersible floating offshore wind turbine. Therefore, the following research question is defined: What is the effect of misaligned wind, windsea waves, and swells on the loads at the tower base of a semi-submersible type floating offshore wind turbine? Several sensitivity studies are conducted to quantify the contribution of yaw-roll coupling effects and aerodynamic damping to the responses and loads. From these studies, it appears that the yaw-roll coupling can increase the response when excited at wind/wave directions in which the structure is asymmetric. The magnitude of this effect is related to the wave peak period (and the resulting wavelength), the angle of misalignment with respect to the structure, and the apparent length of the structure. Also, the lack of aerodynamic damping in the direction of the rotor plane (side-side direction) leads to a noticeable increase in the response, directly or through coupling effects. Finally, the frequency-domain method is compared with the time-domain simulations (BHawC-OrcaFlex) carried out by Siemens Gamesa. Although reasonable agreement is found for the load driving rigid body modes, significant differences in the tower bottom loads are found for the lowest and highest production wind speeds. These results show that misaligned wind and waves can increase the response for headings where the structure is asymmetric due to coupling effects. Wind-wave misalignment leads to an increased response in the direction of the rotor plane due to the lack of aerodynamic damping. In general, the wind-wave misalignment can also have a mitigating effect on the maximum equivalent moment at the tower base, as the aerodynamic damping also reduces the response in the wave frequency range. Furthermore, the comparison shows the need to extend the frequency-domain method with the first tower bending modes and improvement of aerodynamic/mooring property estimation. Based on the findings and the conclusions, the recommendation is to investigate the floater specific sensitivities at an early stage of the design. Future research should focus on: the implementation of tower flexibility, improvement of the quasi-static estimation of mooring stiffness, frequency dependent aerodynamic properties, and implementation of second-order wave forcing.