Large diameter steel catenary risers (SCRs) are considered a cost efficient export riser solution for gas field developments at deep-water sites. However, SCRs are prone to fatigue damage at their interface with the seabed (the touchdown zone, TDZ) and hence accurate estimation of their fatigue life is crucial. The major source of TDZ fatigue damage is the motions of the host vessel subjected to irregular ocean waves. The first-order interaction between the host vessel and the ocean causes oscillations in all degrees of freedom at the same frequencies as the incident waves. The second-order interactions result in a mean-drift offset from the static equilibrium position in the horizontal plane and slowly-varying cyclic motions about that offset position. This paper investigates the effects of second order motions on the fatigue life of a 26” SCR connected to a representative Floating Production Storage and Offload vessel (FPSO), using realistic environmental conditions relevant for a deep-water site on the Australian Northwest Shelf. A diffraction analysis was performed to obtain the hydrodynamic characteristics of the ship-shaped vessel which was subsequently used as the input into a fully coupled response model consisting of the floater, mooring lines and the SCR. A realistic fatigue wave scatter diagram was adopted, consisting of 100 sea-states combining irregular seas, swell, current and winds. This was combined with dynamic time-domain motion analysis and a rainflow cycle counting algorithm in order to determine the fatigue damage within the SCR TDZ due to the host FPSO motions. The results shows that for this representative system the second-order cyclic low frequency (LF) motions have beneficial impacts on fatigue life of the large diameter SCR. Similarly, mean-offsets of the FPSO have a beneficial effect due to changes in the fatigue hotspot location along the SCR within the TDZ for each sea-state. Finally, a simplified method is presented to capture these beneficial effects at the early design stages.