The fatigue behaviour of a powder-metallurgy (PM) + heat-treated Ti49Al47Cr2Nb2 alloy is investigated using detailed SEM characterization. Based on the results of comparative static and cyclic loadings at RT, the fracture origins for the different test specimens is investigated. Conventional fractographic analyses revealed that internal structural defects inherent to powder metallurgy such as compaction defects, porosities and non-metallic inclusions can promote crack initiation. However, the fracture surface of test specimens is markedly affected by the microstructure, which is indicative of the microstructure dependence on crack initiation and propagation. In sub-transus heat treatment conditions, the detrimental effect of structural defects is illustrated by clear crack initiation sites onto the fracture surfaces. In super-transus conditions, crack propagation from defects can be blunted due to crack deflection, branching through lamellar interfaces, thus leading to lower defect sensitivity. Correlation of the results of these microfractographic examinations with the stress-strain curves corresponding to the various specimens allows identifying the role of such structural defects on the static and cyclic deformation behaviours. Finally, implications of such dependencies will be assessed relative to the requirements for aerospace gas turbine applications.