Thermal runaway has been proposed as a potential mechanism to initiate intermediate-depth earthquakes as well as lithospheric-scale shear zones at depths of 50–300km where brittle failure is inhibited due to the confining pressure. Microstructural analyses of mantle shear zones and pseudotachylites, experimental results as well as numerical models suggest that grain size reduction plays a significant role in this process and facilitates the initiation of thermal runaway and thus also the nucleation of intermediate-depth earthquakes as well as the formation of lithosphere-scale shear zones. Here I investigate the impact of complex composite rheologies on grain size assisted thermal runaway using numerical models.Results indicate that diffusion creep, dislocation accommodated grain boundary sliding as well as low-temperature plasticity do have a significant impact on the deformation of mantle rocks under lithospheric conditions and that peak stresses as well as the timing of grain size assisted thermal runaway. Ductile deformation in the shear zone leads to weakening of the rock due to grain size reduction and shear heating. Due to this weakening, the rheological contrasts between the shear zone and the surrounding rock are increased and the critical stress required to initiate thermal runaway is progressively decreased until the rock fails by self-localizing thermal runaway. However, dislocation accommodated grain boundary sliding reduces the temperatures at which this process is feasible, as it weakens the rock to such an extent that critical runaway stresses are never reached.Application of these numerical models to the 2013 Wind River earthquake (Wyoming) suggests that grain size assisted thermal runaway is a feasible mechanism for the nucleation of this earthquake.