T he genetic defect underlying paroxysmal nocturnal hemoglobinuria (PNH) has been shown to reside in PIGA, a gene that encodes an element required for the first step in glycophosphatidylinositol anchor assembly. Why PIGA-mutated cells are able to expand in PNH marrow, however, is as yet unclear. To address this question, we compared the growth of affected CD59^–CD34⁺ and unaffected CD59⁺CD34⁺ cells from patients with that of normal CD59⁺CD34⁺ cells in liquid culture. One hundred FACS-sorted cells were added per well into microtiter plates, and after 11 days at 37°C the progeny were counted and were analyzed for their differentiation pattern. We found that CD59^–CD34⁺ cells from PNH patients proliferated to levels approaching those of normal cells, but that CD59⁺CD34⁺ cells from the patients gave rise to 20- to 140-fold fewer cells. Prior to sorting, the patients’ CD59^– and CD59⁺CD34⁺ cells were equivalent with respect to early differentiation markers, and following culture, the CD45 differentiation patterns were identical to those of control CD34⁺ cells. Further analyses of the unsorted CD59⁺CD34⁺ population, however, showed elevated levels of Fas receptor. Addition of agonist anti-Fas mAb to cultures reduced the CD59⁺CD34⁺ cell yield by up to 78% but had a minimal effect on the CD59^–CD34⁺ cells, whereas antagonist anti-Fas mAb enhanced the yield by up to 250%. These results suggest that expansion of PIGA-mutated cells in PNH marrow is due to a growth defect in nonmutated cells, and that greater susceptibility to apoptosis is one factor involved in the growth impairment.