Oral contraceptives and postmenopausal estrogen replacement therapy are recognized as risk factors for the development of porphyria cutanea tarda (PCT) in women. The recommended clinical practice is to withhold estrogen therapy in women who have had phlebotomy therapy for PCT and are clinically and biochemically normal. We tested the safety and efficacy of transdermal estrogen replacement therapy in 7 women previously treated for PCT and compared them with 19 non-porphyric control subjects treated with transdermal or oral estrogens. Gonadotrophic hormone levels, estrogen levels, liver function studies, body iron stores, urine porphyrin excretion, and cytochrome P4501A2 (CYP1A2) activity were monitored for 1 year. Four of the women previously treated for PCT completed the study. None had evidence of a porphyric relapse. CYP1A2 activity, measured by three different methods, did not differ between study subjects receiving estrogens, patients with active PCT, and non-porphyric control subjects, nor did CYP1A2 activity change during the study period. Gonadotrophic hormone levels fell and estrogen levels rose in all women receiving estrogens. The administration of estrogens by the transdermal route appeared to be safe in the small number of subjects we studied and should be considered for women previously treated for PCT.