The corpus callosum is the largest connection between the functionally asymmetric cerebral hemispheres. The objective of this study was to measure functional activity of callosal fiber tracts during speech processing. We analyzed the regional glucose metabolism of the corpus callosum and of speech-relevant cortical areas in 10 normal individuals at rest and during word repetition. We used three-dimensionally registered magnetic resonance imaging to visualize the individual brain morphology and high-resolution positron emission tomography for metabolic measurements. The task-induced metabolic changes of the callosal midbody and isthmus had a significant negative correlation with key regions of language processing in the left inferior frontal cortex (Brodmann's area 44) and in the right superior temporal cortex (Brodmann's area 22) (e.g., correlation of metabolic changes in the surface aspects of the right Brodmann's area 22 and the callosal midbody/isthmus: r = -0.91, P < 0.001). The study indicates that language processing in asymmetrically organized cortical areas inhibits the reciprocal transcallosal information exchange in favor of the lateralized mental operation. Our data agree with anatomic, electrophysiologic, and pharmacologic experiments that point to the important role of collateral inhibition for the transcallosal information exchange.