Inhibition of return refers to a slower responding to a target stimulus appearing at previously cued locations. We used the event-related potentials technique to investigate the effects of inhibition of return in semantic processing with the combination of a spatial cueing task and semantic N400 paradigm. The results showed that the N400 component, as an index of semantic processing, was suppressed when the target words were presented in the cued location relative to the uncued location. The results indicated that the semantic processing of the target word presented on the cued location is affected by inhibition of return. Moreover, our findings provided event-related potential evidence for the inhibition of attention theory of inhibition of return.