The detection of novel events and their identification is a basic prerequisite in a rapidly changing environment. Recently, the processing of novelty has been shown to rely on the hippocampus and to be associated with activity in reward-related areas. The present study investigated the influence of spatial attention on neural processing of novel relative to frequently presented standard and target stimuli. Never-before-seen Mandelbrot-fractals absent of semantic content were employed as stimulus material. Consistent with current theories, novelty activated a widespread network of brain areas including the hippocampus. No activity, however, could be observed in reward-related areas with the novel stimuli absent of a semantic meaning employed here. In the perceptual part of the novelty-processing network a region in the lingual gyrus was found to specifically process novel events when they occurred outside the focus of spatial attention. These findings indicate that the initial detection of unexpected novel events generally occurs in specialized perceptual areas within the ventral visual stream, whereas activation of reward-related areas appears to be restricted to events that do possess a semantic content indicative of the biological relevance of the stimulus. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc.