A new theory of fatigue crack growth in ductile solids has recently been proposed based on the total plastic energy dissipation per cycle ahead of the crack. This and previous energy based approaches in the literature suggest that the total plastic dissipation per cycle can be closely correlated with fatigue crack growth rates under mode I loading. In a recent paper, the authors have extended the dissipated energy approach to the case of fatigue crack growth in a homogeneous material under sustained mixed-mode loading conditions. The goal of the current study is to further extend the approach to mixed-mode fatigue delamination of ductile interfaces in layered materials. Attention is restricted to material combinations with identical elastic properties, but with mismatches in plastic properties (both yield strength and hardening modulus) across the interface. Such systems can occur in brazing, soldering, welding, and a variety of layered manufacturing applications, where high-temperature material deposition can result in a mismatch in mechanical properties between the deposited material and the substrate. In this study, the total plastic dissipation per cycle is obtained through plane strain elastic–plastic finite element analysis of a stationary crack in a general layered specimen geometry under constant amplitude, mixed-mode loading. Numerical results for a dimensionless plastic dissipation per cycle are presented over the full range of relevant material combinations and mixed-mode loading conditions. Results suggest that while applied mode-mix ratio is the dominant parameter, mismatches in yield strength and hardening modulus can have a significant effect on the total plastic dissipation per cycle, which is dominated by the weaker/softer material.