The effect of yttrium (Y)-containing particles on the microstructure and fatigue behavior of investment-cast and hot isostatically pressed (HIP) Ti-6Al-4V has been investigated. Elemental Y was added to the Ti-6Al-4V melt to obtain a concentration of 200 ppm Y, which is 4 times the amount allowed by current industrial specifications. The observed particles were between 100 nm and 1 lm in diameter, were widely dispersed, and did not agglomerate. High-cycle fatigue tests were conducted and an extensive fractography study revealed that the effect of the particles was negligible compared to the large colony size, and therefore slip length, in the cast material. The fatigue lives were consistent with those in the literature for tests conducted on specimens containing standard concentrations of Y. A section of the casting was extruded to refine the grain size in order to study the effects of the particles on a microstructure with shorter slip lengths. The results of the fractography study on these specimens were not as straightforward. A fine particle was observed at the crack-initiation site of one of the specimens of extruded material and shallow depressions on the size scale of the particles were present in other samples. However, no evidence of Y was detected by energy-dispersive spectroscopy (EDS) and the fatigue lives were on the high end of the scatter band typically encountered in wrought and annealed Ti-6Al-4V.