The purpose of this paper is to investigate the differences in mechanical response and microstructural behavior when the single-crystal Ni-based superalloy CMSX-4 is subjected to thermomechanical fatigue (TMF) in two di↵erent crystallographic directions, <001> and <011>. An out-of-phase (OP) straincontrolled TMF cycle with R ✏ =-1 in the temperature range 100 to 850 C was used. As expected, the material exhibited, when loaded in the <001> direction, a higher number of cycles to failure compared to the <011> direction, when equivalent strain ranges were compared. High strain ranges led to crystallographic fractures along one of the {111} planes while low strain ranges led to non-crystallographic fractures. This result was valid for both <001> and <011> directions. Specimens with random fractures also showed recrystallization close to the fracture surface. Twinning was found to be a major deformation mechanism for most specimens. A change in deformation mechanism from twinning to shearing was found in specimens subjected to loading in the <011> direction when going from low to high strain ranges. This investigation also indicated that crack propagation is a consequence of recrystallization and not the other way around.