The influence of iron (Fe)-containing constituent particles on the behavior of fatigue crack initiation and propagation of Al-Cu-Li-Mg-Zr alloys has been studied using fatigue crack growth (FCG) tests and in-situ fatigue testing and detailed metallographic examination based on scanning electron microscopy. Experimental results show that the alloy with a low level of Fe content (2A97-T3 sheet) exhibited a lower density, accompanying equivalent tensile strength and FCG rate compared to the damage-tolerant 2524-T3 sheet. It was found that the fatigue b growth of both alloys is dominated by transgranular mode, accompanied by intergranular expansion, and the high level of Fe content alloy presents more characteristics of intergranular. Coarse constituent particles were detrimental to the resistance against FCG. It is postulated here that the micro-cracks formed around the coarse Fe-containing particles are merged with the primary crack to produce a bridging effect, accelerating the growth of fatigue cracks in the alloy with a high level of Fe content.