Detection of a Gabor pattern is impaired in the presence of a similar pattern of orthogonal orientation, a phenomenon known as cross-orientation masking (XOM). Here we investigate the role of color in cross-orientation masking. We measured contrast detection thresholds to horizontally oriented Gabors overlaid by similar Gabors of a different orientation. Red-green chromatic masking was compared to achromatic masking for a wide range of spatial and temporal frequencies, orientations, and masks contrasts. We find that cross-orientation masking is significantly greater for chromatic than achromatic contrast. We also find it is invariant with the spatio-temporal conditions used, unlike achromatic cross-orientation masking that is known to have a spatio-temporal dependence (greatest for low spatial frequencies at high temporal frequencies). Furthermore, chromatic masking is isotropic (invariant across the orientation difference between test and mask), whereas the achromatic version of the masking effect displays orientation tuning, a phenomenon that was originally used to indicate the presence of orientationally selective mechanisms in human vision. We conclude that the P cell pathway or its projections can support cross-orientation masking. We propose distinct physiological origins for chromatic and achromatic masking, with a predominantly cortical site for chromatic masking in contrast to the M cell subcortical influences on achromatic masking suggested by previous studies.