Numerous studies have reported neurophysiological effects of semantic priming in electroencephalography (EEG) and in functional magnetic resonance imaging (fMRI). Because of differing methodological constraints, the comparability of the observed effects remains unclear. To directly compare EEG and fMRI effects and neural sources of semantic priming, we conducted a semantic word-picture priming experiment while measuring EEG and fMRI simultaneously. The visually presented primes were pseudowords, words unrelated to the target, semantically related words and the identical names of the target. Distributed source analysis of the event-related potentials (ERPs) successfully revealed a large effect of semantic prime-target relatedness (the N400 effect), which was driven by activations in a left-temporal source region. However, no significantly differing activations between priming conditions were found in the fMRI data. Our results support the notion that, for joint interpretations of existing EEG and fMRI studies of semantic priming, we need to fully appreciate the respective methodological limitations. Second, they show that simultaneous EEG-fMRI, including ERP source localization, is a feasible and promising methodological advancement for the investigation of higher-cognitive processes. Third, they substantiate the finding that, compared to fMRI, ERPs are often more sensitive to subtle cognitive effects.