The frontal lobes have long been implicated in inhibitory control, but a full understanding of the underlying mechanisms remains elusive. The stop-signal task has been widely used to probe instructed response inhibition in cognitive neuroscience. The processes involved have been modeled and related to putative brain substrates. However, there has been surprisingly little human lesion research using this task, with the few existing studies implicating different prefrontal regions. Here, we tested the effects of focal prefrontal damage on stop-signal task performance in a large sample of people with chronic focal damage affecting the frontal lobes (n = 42) and demographically matched healthy individuals (n = 60). Patients with damage to the left lateral, right lateral, dorsomedial, or ventromedial frontal lobe had slower stop-signal RT compared to healthy controls. There were systematic differences in the patterns of impairment across frontal subgroups: Those with damage to the left or right lateral and dorsomedial frontal lobes, but not those with ventromedial frontal damage, were slower than controls to “go” as well as to stop. These findings suggest that multiple prefrontal regions make necessary but distinct contributions to stop-signal task performance. As a consequence, stop-signal RT slowing is not strongly localizing within the frontal lobes.