Representing the orientation of features in the visual image is a fundamental operation of the early cortical visual system. The nature of such representations can be informed by considering anisotropic distributions of response across the range of orientations. Here we used functional MRI to study modulations in the cortical activity elicited by observation of a sinusoidal grating that varied in orientation. We report a significant anisotropy in the measured blood-oxygen level-dependent activity within visual areas V1, V2, V3, and V3A/B in which horizontal orientations evoked a reduced response. These visual areas and hV4 showed a further anisotropy in which increased responses were observed for orientations that were radial to the point of fixation. We speculate that the anisotropies in cortical activity may be related to anisotropies in the prevalence and behavioral relevance of orientations in typical natural environments.