Blade nickel superalloy CMSX-4 widely used in the aero industry and its potential low cost alternative, superalloy CM186LC intended for use in the industrial gas turbines, were subjected to ultra-high-cycle fatigue at high mean stresses to model the effect of vibrations superimposed on sustained load. Circumferentially notched cylindrical specimens of single crystals with the axis orientation of [001] were tested at 850 °C in air. For small amplitudes of the cyclic stress superimposed on the sustained stress the time to fracture is slightly increasing with increasing stress amplitude. This trend is reversed for higher stress amplitudes where the time to fracture quickly decreases with increasing stress amplitude. Fatigue crack initiation and following crack propagation are here the decisive failure mechanisms. Cyclic stress component leads to the formation of persistent slip bands running through the γ matrix and the γ′ precipitates. These bands represent sites for the initiation (in interaction with casting pores and other defects) and early propagation of fatigue cracks. The early crack propagation along the slip planes is later replaced by non-crystallographic propagation of the dominant crack.