The influence of microstructure on mixed-mode (mode I+II) high-cycle fatigue thresholds in a Ti-6Al-4V alloy is reported for crack sizes ranging from tens of micrometers to in excess of several millimeters. Two particular microstructural conditions were examined: a fine-grained equiaxed bimodal microstructure structure (grain size similar to20 mum), and a coarser lamellar structure (colony size similar to500 mum). Studies were conducted over a range of mode-mixities, from pure mode I (DeltaK(II)/AK(I) = 0) to nearly pure mode II (AK(II)/AK(I) similar to 7.1), at load ratios (minimum load/maximum load) of 0.1, 0.5 and 0.8. The thresholds were characterized in terms of the strain-energy release rate (AG) incorporating both tensile and shear loading components. In the presence of through-thickness cracks, large (>4 mm) compared to the microstructural dimensions, significant effects of mode-mixity and load ratio were observed for both structures, with the lamellar alloy generally displaying better resistance. However, these effects were substantially reduced if allowance was made for crack-tip shielding. Furthermore, when thresholds were measured in the presence of cracks comparable to the microstructural dimensions, specifically through-thickness short (similar to200 mum) cracks and microstructurally-small (<50 mum) surface cracks, where the influence of crack-tip shielding is minimal, such effects were similarly reduced. Indeed, small-crack DeltaG(TH) thresholds were some 50 to 90 times lower than the corresponding large crack values. These results are discussed in terms of the dominant role of mode I behavior and the effect of microstructure (in relation to crack size) in promoting crack-tip shielding that arises from significant changes in the crack path in the two microstructures.