High-temperature fatigue behavior of a near-γ titanium aluminide was studied over the temperature range from 500–750 °C under both isothermal and thermomechanical fatigue (TMF) conditions. Cyclic stress-strain (CSS) response was observed to change drastically with test temperature. In isothermal tests conducted below the ductile-to-brittle transition temperature (DBTT) initial cyclic hardening occurred. By contrast, in isothermal fatigue tests performed above the DBTT the material displayed pronounced cyclic saturation throughout the test. Still, modeling of CSS behavior under TMF conditions based solely on isothermal input data is feasible, as corresponding microstructures evolve in both types of tests. Environmental degradation plays a key role in this material, and the effects were assessed based on fatigue tests conducted in air and high-vacuum, respectively. Moreover, the material displays large mean stress effects below the DBTT, and thus, out-of-phase TMF tests were found to be most detrimental, when the temperature range encompassed the DBTT.