The contingent negative variation (CNV) is a brain potential generated during delay periods that has been proposed to measure prefrontal cortex (PFCx) activity. The CNV was recorded in neurological patients with PFCx damage centered in Brodmann areas 9, 44, 45, and 46 in a classical auditory S1-S2 paradigm employing a 3 sec interstimulus interval. Subjects pressed a button upon detection of an acoustically cued imperative tone (S2, 1000 Hz, GO). Responses were withheld if the warning tone (S1, 1500 Hz in GO trials) was lower in frequency (500 Hz, NOGO). The early phase of the CNV (500–700 msec after S1) was not reduced in patients with PFCx damage. PFCx lesions reduced the later phase of the CNV beginning about 1000 msec prior to S2. Reductions were maximal over PFCx sites but extended to posterior scalp electrodes over the lesioned hemisphere. The results are consistent with a late CNV generator in dorsolateral PFCx that also modulates generation of the potential in posterior regions of the ipsilateral hemisphere. The CNV findings coupled with behavioral evidence of impaired preparatory processes in these patients support the role of PFCx in sustaining distributed neural activity during delay periods.