In two male patients with acute hepatic porphyria and persisting paralysis which increased in intensity intermittently, the activity of porphobilinogen synthase (PBG-S; delta-aminolevulinic acid dehydr(at)ase) was diminished in peripheral erythrocytes and bone marrow cells below 3% of normal controls. In contrast, the activities of uroporphyrinogen synthase and decarboxylase were normal. Both patients have been excreting high quantities of delta-aminolevulinic acid and porphyrins in urine for years. Lead intoxication and tyrosinemia could definitely be excluded. There was no experimental evidence for the existence of an inhibitor to PBG-S in urine, serum and erythrocytes from these two patients. The PBG-S deficiency was confirmed after DEAE cellulose chromatography: the concordance of relative and specific activity before and after chromatography of PBG-S from patients and controls differs from the findings in lead poisoning. A mutation of PBG-S probably at the level of the structural gene is concluded as the molecular basis of the inherited PBG-S defect porphyria. Since the relatives also show lower activities of PBG-S (approximately 50% of controls), the disease of these two patients represents a new enzymatic type of inherited acute hepatic porphyria, the excretion profile of which is qualitatively completely different from those of the known acute porphyrias. The discovery of this porphyria confirms the theory of overlapping transition in the biochemical signs and clinical symptoms as well as analogies among the acute hepatic porphyrias and lead poisoning.