The effect of crystallographic orientation and sample volume on incipient plasticity of commercially pure polycrystalline nickel 200 was investigated using electron back scatter diffraction (EBSD) and nanoindentation. A nickel sample was annealed, and grain orientations were determined using EBSD. Specifically oriented grains were indented using tips of nominal radii 100, 1000, and 1300 nm. The onset of plasticity in relatively defect-free small volumes is characterized by a sharp “pop-in” event during load-controlled nanoindentation. Grains in the (001) orientation yield at higher pressures; larger radii tips are more sensitive to orientation effects but yield at lower stresses. Subsurface defects may result in the dominance of tip radius over orientation, indicated by statistical analysis of yield points. An activation volume analysis, in conjunction with the yield pressure as a function of tip size, suggests that dislocation loops may play a critical role in causing these effects.