Strain-controlled out-of-phase thermo-mechanical fatigue tests at 100–500 °C and various strain ranges were conducted on five cast iron grades, including one lamellar, three compacted and one spheroidal graphite iron. Investigations of graphite morphology and matrix characteristics were performed to associate parameters, such as geometrical features of graphite inclusions and the matrix microhardness, to the thermo-mechanical fatigue performance of each grade. From this, thermo-mechanical fatigue life as a function of maximum stress at half-life, is found to decrease consistently with increasing average graphite inclusion length irrespective of the graphite content. In contrast, no evident correlation between the fatigue life and the matrix microhardness is observed.