Isothermal and thermo-mechanical fatigue (TMF) behavior of a dispersion-strengthened aluminum alloy has been studied between room temperature and 350°C. Cyclic stress-strain (CSS) response was found to be dominated by dispersoid-dislocation interactions, and thus, the effect of an additional SiC reinforcement on CSS behavior was only minor. As the dispersoids are thermally very stable, identical microstructures were observed to form independent of the actual loading conditions. Consequently, CSS response under TMF conditions could be accurately predicted from isothermal tests only. Damage evolution, by contrast, was found to depend drastically on the type of test. A microcrack propagation model could be successfully used to correlate all tests performed on the unreinforced alloy. In the SiC-reinforced material, however, both creep damage and oxidation damage were more severe under TMF conditions than predicted from isothermal tests, and life prediction is nonconservative, if only based on isothermal tests.