Upscaling of traditional monopiles to support larger offshore wind turbines introduces fatigue-related design challenges. The design becomes mainly driven by wave-induced fatigue loads, and potential resonant responses can have significant contributions to fatigue. It is essential that these changes in load characteristics be reflected in the design codes. In this paper, fatigue reliability analysis of a wave sensitive, large monopile supporting a 10 MW offshore wind turbine is demonstrated. Reliability-based calibration of fatigue design factors is based on an extensive set of numerical simulations, where the statistical distribution of turbulence intensity and preservation of wave-induced resonant responses are considered. Results show that a minimum fatigue design factor, FDF⩾3 is recommended. The results and methodology presented in this study can assist with identifying the technical limitations and economic viability of upscaling monopiles.