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Fe epitaxy on Cu(100) is investigated for Fe coverages θ≤3.0 ML. The layer filling statistics are quantitatively related to an evolving growth process, which includes intermixing at the substrate overlayer interface. The resulting inhomogeneous substrate surface and first layer affect the processes by which arriving Fe atoms add to the growth front. Our results explain the previously reported covering of initial Fe not as bilayer growth, but instead as the result of island growth on top of Fe incorporated in the top substrate layer. First layer composition and structure influence the nucleation and growth of the second layer. Island coalescence and formation of a first layer percolation network change the connected first layer area thereby changing the nucleation and growth behavior of the second layer. After both first and second layer growth are completed, images show additional growth is much more layer‐by‐layer in nature. Oxygen exposure after Fe deposition changes the layer filling by both promotion of step crossing and expansion of partially filled Fe layers.