A simulation analysis of the impact that the nonlinear response of a semiconductor optical amplifier (SOA) has in a four-channel WDM pre-amplified transmission system is presented in the framework of the recently proposed extended-reach (40-km, 4 × 25 Gb/s) 100 Gb Ethernet link. Channel spacing values ranging from 200 to 800 GHz, and fiber losses between 0 and −20 dB are considered. A maximum power penalty of 4.5 dB is predicted for short fiber lengths and for the tightest channel plan. For short fiber lengths, the penalty drops by about 0.8 dB when moving from 400 to 800 GHz; whereas for long fiber lengths, the penalty increases by 0.2 dB, provided that an average dispersive fiber is utilized. The widely spaced channel plan then represents the best choice in terms of the analyzed physical effects to implement the next-generation 100 GbE link. Further, our numerical investigation includes a discrimination analysis that confirms cross-gain modulation as the main overall SOA nonlinear impairment in the analyzed architecture, and establishes ultra-fast carrier heating-induced FWM as responsible for the system performance difference observed as a function of channel spacing. The difference practically vanishes for fiber lengths above 30 km. Finally, the proposal of an equation that fits the simulated power spectrum density of the first-order four-wave mixing-generated product as a function of channel spacing is presented as an aid to validate our numerical results.