The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET) during overt word and nonword reading tasks to determine structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12 times, twice in each of six specific conditions. Blood flow was measured by 15O-water using standard PET imaging technology. The rCBFs during different cognitive conditions were compared by using analysis of covariance (SPM94), which resulted in three-dimensional maps of those brain regions more active in one condition relative to another. When the subjects read aloud words with difficult or unusual grapheme-phoneme translations (i.e., third-order approximation to English or irregularly spelled real words), increases in activation were seen in the inferior frontal cortex. When subjects were reading aloud regular and irregular words (which had important semantic components relative to nonwords), activation of the fusiform gyrus was seen. These data are broadly consistent with brain regions generally associated with reading based on other neuropsychological paradigms, and they emphasize the multicomponent aspects of this complex cognitive process.