The present study explored constraints on mid-fusiform activation during object discrimination. In three experiments, participants performed a matching task on simple line configurations, nameable objects, three dimensional (3-D) shapes, and colors. Significant bilateral mid-fusiform activation emerged when participants matched objects and 3-D shapes, as compared to when they matched two-dimensional (2-D) line configurations and colors, indicating that the mid-fusiform is engaged more strongly for processing structural descriptions (e.g., comparing 3-D volumetric shape) than perceptual descriptions (e.g., comparing 2-D or color information). In two of the experiments, the same mid-fusiform regions were also modulated by the degree of structural similarity between stimuli, implicating a role for the mid-fusiform in fine differentiation of similar visual object representations. Importantly, however, this process of fine differentiation occurred at the level of structural, but not perceptual, descriptions. Moreover, mid-fusiform activity was more robust when participants matched shape compared to color information using the identical stimuli, indicating that activity in the mid-fusiform gyrus is not driven by specific stimulus properties, but rather by the process of distinguishing stimuli based on shape information. Taken together, these findings further clarify the nature of object processing in the mid-fusiform gyrus. This region is engaged specifically in structural differentiation, a critical component process of object recognition and categorization.