To assess the effect of iron (Fe) content on the properties of M5™, several industrial-sized ingots with Fe content up to 1000 ppm and some smaller ingots with Fe up to 1300 ppm have been manufactured, tested, and investigated. The evolution of the microstructure with iron content has been both experimentally determined and theoretically assessed with thermodynamic computations, showing that iron in the investigated range has only a slight impact on the balance between the two classical second-phase precipitates observed in M5™: β-Nb and Laves phase. Moreover, it was found that the impact of iron on texture and mechanical properties, including thermal creep, is null. Out-of-pile autoclave corrosion tests show, on the one hand, that the iron content has no effect in 360°C primary water environment and little effect in 400°C–415°C steam. On the other hand, iron content in the range of 300 to 1000 ppm improves the resistance to corrosion induced by galvanic phenomena. This phenomenon has been reproduced out-of-pile in galvanic coupling tests in 360°C oxygenated water. In-pile, the corrosion resistance is equivalent, or even improved, under demanding conditions when the iron content is increased. There is no adverse effect of iron content on free growth kinetics and creep behavior. Under loss of cooling accident (LOCA) conditions, the increase in iron content has no significant impact on creep–burst resistance and ductility of the cladding. The high-temperature steam oxidation kinetics, quench behavior, and post-quench behavior of fresh and pre-hydrided materials are not affected. Finally, because of the low hydrogen pickup of M5™ in service, which is unchanged by increased iron content, the high performance of M5™ under reactivity-initiated accident (RIA) conditions is not impacted.