Four-dot masking is a new form of visual masking that does not involve local contour interactions or spatial superimposition of the target stimulus and the mask (as, e.g., in pattern or metacontrast masking). Rather, the effective masking mechanism is based on object substitution. Object substitution masking occurs when low-level visual information representations are altered before target identification through iterative interaction with high-level visual processing stages has been completed. Interestingly, object substitution interacts with attention processes: Strong masking effects are observed when attentional orientation toward the target location is delayed. In contrast, no masking occurs when attention can be rapidly shifted to and engaged onto the target location. We investigated the neural basis of object substitution masking by studying the interaction of spatial attention and masking processes using functional magnetic resonance imaging. Behavioral data indicated a two-way interaction between the factors Spatial Attention (valid vs. invalid cueing) and Masking (four-dot vs. pattern masking). As expected, spatial attention improved performance more strongly during object substitution masking. Functional correlates of this interaction were found in the primary visual cortex, higher visual areas, and left intraparietal sulcus. A region-of-interest analysis in these areas revealed that the largest blood oxygenation level-dependent signal changes occurred during effective four-dot masking. In contrast, the weakest signal changes in these areas were observed when target visibility was highest. The data suggest that these areas represent an object substitution network dedicated to the generation and testing of a perceptual hypotheses as described by the object substitution theory of masking of Di-Lollo et al. [Competition for consciousness among visual events: The psychophysics of reentrant visual processes. Journal of Experimental Psychology: General, 129, 481–507, 2000].