Behavior of thermo-mechanical fatigue (TMF) of a single crystal Ni-base superalloy, CMSX-4, was studied, compared with that of isothermal low-cycle fatigue (LCF). Strain-controlled TMF and LCF tests of CMSX-4 were carried out under various test conditions, where the experimental variables were strain rates, strain ratio, temperature range, and strain/temperature phase angle. At first it was shown experimentally that the TMF and LCF failures took places, associated with some noteworthy characteristics which were rarely seen in the traditional polycrystalline heat resistant alloys. They could not be explained reasonably, based on the historical approaches. A new micromechanics model was proposed to predict the TMF and LCF lives, applying the Eshelby’s theory and the Mori-Tanaka’s averaging approximation. The model presented in this paper enabled us to successfully estimate not only the unique characteristics in the TMF and LCF failures but also the effect of γ’ geometry on the LCF lives.