Porphyria cutanea tarda (PCT) results from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). Both sporadic and familial forms are characterised by typical cutaneous lesions triggered by genetic/environmental factors. Studies in rodents showed that cytochrome P4501A2 (CYP1A2) plays a central role in the synthesis of a competitive inhibitor of hepatic UROD, but there is little evidence in humans. The impact of smoking and CYP1A2 g-163C > A allelic variant upon first appearance of clinical signs was investigated in 102 patients (80 sporadic-PCT) and 150 healthy donors from Spain. We found an increase in the frequency of CYP1A2 g-163A allele in patients with PCT when compared with controls, although the more inducible A/A genotype had no effect on the onset age. In sporadic-PCT, smoking leads to earlier onset of clinically overt disease in moderate-to-heavy smokers (>or=10 cigarettes/day). In conclusion, this study provides evidence that smoking hastens the onset of cutaneous symptoms in sporadic-PCT patients.