The near alpha titanium alloy, Ti-6424S, is utilized in manycritical high-temperature aerospace components due to its unique properties. However, oxygen ingress during elevated-temperature exposure induces formation of a subsurface brittle oxygen-rich layer (ORL), resulting in a deterioration of mechanical performance. This paper, for the first time, establishes the effect of the underlying microstructure on the formation and evolution of the ORL inα/β titanium alloys.In addition, models were developed to predict (i) the evolution of ORL as a function of the material microstructure, (ii) the effect of ORL on the critical strain for in-service crack initiation, and (iii) estimates of fatigue life of components made from a specific microstructure during in-service high temperature exposure and formation of ORL. In particular, five different microstructures wereproducedby tailored heat-treatments and thermally exposed at 650°C up to 420 hrs. The base metal and the ORL were quantified using microhardness indentations, optical microscopy, and scanning electron microscopy (electron backscatter diffraction (EBSD), backscattered electron (BSE), and secondary electron (SE) imaging). The effective diffusion coefficients (D eff) for each microstructure were calculated and then integrated into a critical strain model to predict crack initiation strain as a function of exposure time. The predicted ORL thickness was used to estimate fatigue life using experimentally measured crack growth data.The largest D eff coefficient was observed in a colony microstructure, whilea basketweave microstructure showed the smallestD eff. For several bimodal microstructures, D eff was noted to increase with increasing area fraction of secondary alpha colonies.