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In this study, the difference between in-phase (IP) and out-of-phase (OP) thermomechanical fatigue (TMF) cycling at 100–850 °C of a single-crystal superalloy is investigated both from a mechanical response and resulting microstructure perspective. Results indicate that there is no significant difference in fatigue lives between IP and OP TMF when similar strain ranges and crystal orientations are considered. The deformation mechanisms occurring during IP and OP TMF are similar where the main deformation mechanism for this alloy is localized deformation bands and crack initiation is preferred to these bands. Other TMF mechanisms, such as recrystallization and oxidation, are also discussed.