The erythropoietic porphyrias, erythropoietic protoporphyria and congenital erythropoietic porphyria, result from germline mutations in the ferrochelatase gene and uroporphyrinogen III synthase gene, respectively. Both conditions normally present in childhood but rare cases with onset past the age of 40 y have been reported. Here we show that late-onset erythropoietic protoporphyria can be caused by deletion of the ferrochelatase gene in hematopoietic cells with clonal expansion as part of the myelodysplastic process. This is the first direct demonstration of porphyria produced by an acquired molecular defect restricted to one tissue. Some other cases of late-onset erythropoietic porphyria may be explained by a similar mechanism.