Several studies have shown that cortical damage, especially to the right hemisphere and to frontal lobes, may attenuate skin conductance responses selectively to psychologically significant stimuli. We tested this hypothesis in 32 patients with frontal lesions, verified by computer assisted tomography and magnetic resonance imaging, and 45 healthy controls. Patients and controls were given a protocol which included a rest period, a series of innocuous tones, and a reaction time task. Patients were given a second protocol in which they viewed slides with positive and negative emotional content and neutral slides. Results showed attenuated electrodermal activity (EDA) during task instructions and smaller skin conductance responses to reaction-time stimuli in patients compared to controls but few differences under passive conditions or in orienting responses to simple tones. Patients with lateral prefrontal and paraventricular lesions were especially low in EDA in the reaction time task, and those with right and bilateral lesions in the cingulate gyrus and/or frontal operculum had attenuated EDA in both protocols. We conclude that the effects of certain frontal lesions are on the psychological response to significance which is indexed by EDA rather than directly on EDA per se.