Many common clinical features suggest that between corticosuprarenal insufficiency (CSRI) and porphyria cutanea tarda (PCT) there may be some pathogenic relationships. In order to further understand these relations we have performed the ACTH-depot stimulation test (1 mg, i.m.) in 9 patients (from 13 males) with PCT. In 8 patients cortisolemia was assayed 1, 2, (12) and 24 hours post-stimulation. In all 13 cases the basal eliminations of cortisol metabolite (17-OH-corticosteroids) were under normal limits: 2.88 mg/24 h/g creatinine vs 15 controls with 7.06 mg/24h/g creatinine. After ACTH four cases showed lack of stimulation, considered on the second day for 17-OH-corticosteroids. In one case, after one year of PCT treatment, the early post-stimulation level is only moderately decreased. In one case, the test was normal. In four cases the ACTH stimulation was over-normal, i.e., greater than on the first day, suggesting supraphysiological responses. In this group 2 patients showed unexpectedly low early stimulation slopes on cortisolemia (at 1 and 2 hours) associated with concordant high late stimulation levels. This later phenomenon suggests a functional impaired secretion of cortisol in PCT, which seems to be similar to that of insulinemia after glucose in NIDDM, as a receptor lesion. The lesions of cortisol secretion in PCT could have been made by porphyrin storage, impaired hem-enzyme synthesis (cyt P-450) and as a new and attractive hypothesis, could be due to mitochondrial porphyrin receptor decreased activity.