Mixed-mode, high-cycle fatigue-crack growth thresholds are reported for through-thickness cracks (large compared to microstructural dimensions) in a Ti-6Al-4V turbine blade alloy in both lamellar and bimodal microstructural conditions. Specifically, the effect of combined mode I and mode II loading, over a range of phase angles ( ϭ tan Ϫ1 (⌬K II /⌬K I )) from 0 to 62 deg (⌬K II /⌬K I ϳ 0 to 1.9), is examined at a load ratio (ratio of minimum to maximum loads) of R ϭ 0.1 and a cyclic loading frequency of 1000 Hz in ambient-temperature air. When the mixed-mode, crack-driving force is characterized in terms of the strain-energy release rate (⌬G), incorporating contributions from both the applied tensile and shear loading, the threshold for fatigue-crack growth is observed to increase significantly with the applied mode-mixity (⌬K II /⌬K I ) for both microstructures, an effect attributed to enhanced crack-tip shielding. The pure mode I threshold, in terms of ⌬G TH , is observed to be a lower bound (worst case) with respect to mixed-mode (I ϩ II) behavior. For large crack sizes, the threshold fatigue-crack growth resistance of the lamellar structure is observed to be superior to that of the bimodal material for all phase angles investigated. Consideration of mode I fatigue-crack growth thresholds for small cracks in these same microstructures suggests that this rank ordering of mixed-mode fatigue resistance may not hold for crack lengths that are comparable to microstructural size scales. Examination of the fatigue-crack wake indicates that, for the lamellar microstructure, the path of crack extension is significantly influenced by the local microstructure over length scales on the order of the relatively coarse lamellar colonies (ϳ500 m). Comparatively, the crack path in the bimodal material is more strongly influenced by the applied crack-driving force. This disparity in behavior is attributed primarily to the relatively heterogeneous crack-growth resistance of the coarse lamellar microstructure.