Severe aplastic anemia can be successfully treated with immunosuppressive therapies (IST) or hematopoietic stem cell transplantation (HSCT). Response rates with horse anti-thymocyte globulin (ATG) plus cyclosporine (CsA) are about 60–70%, and robust responders have excellent long term survival (Rosenfeld, Follmann et al. 2003). Relapse require reinstitution of IST and does not negatively affect survival. We introduced a third immunosuppressive agent to standard horse ATG/CsA, mycophenolate mofetil, in an attempt to improve response rate, survival and to decrease the relapse rate and clonal evolutions to myelodysplasia or leukemia. MMF blocks the proliferation of active lymphocytes by the inhibition of the enzyme inosine monophosphate dehydrogenase, an important step in purine and therefore DNA synthesis. MMF immunosuppression is due to direct inhibition of T cell proliferation and therefore, would be anticipated to favor the induction of tolerance by selective depletion of active lymphocytes. MMF has been employed as a “kidney-sparing” adjunct to CSA in renal and other solid organ transplantations, post-HSCT, and in certain autoimmune diseases with a favorable toxicity profile. A total of 104 consecutive patients with SAA were treated with horse ATG/CsA/MMF from May 1999 to June 2003 at the Warren Grant Magnuson Clinical Center at the National Institutes of Health in Bethesda, MD. Response was defined by blood counts no longer satisfying criteria for severe AA. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 days from ATG. Fifteen relapses occurred after CsA was discontinued at 6 months but before 18 months, while patients were still on MMF. Nine patients showed evidence of clonal evolution following ATG, five responders and 4 nonresponders. The median survival among responders was not reached and among nonresponders was 1,759 days. There was no difference in overall survival among patients who relapsed and those who did not relapse. Over half of the relapses occurred during MMF administration (15 of 24), suggesting that this drug is not active in preventing relapses among responders. Evolution to clonal disorders did not change with the intensification of immunosuppression with MMF. Despite a strong theoretical rationale for its use, MMF did not result in improvement in response or relapse rates, and it cannot be routinely recommended as a CsA-sparing agent in responders with poor tolerability to CsA.