We evaluated the in vitro effect on clonogenic potential (CFU-GM) and apoptosis in myelodysplastic syndromes (MDS) progenitors of an anti-oxidant (N-acetylcysteine, NAC) and/or a differentiating (all-trans retinoic acid, ATRA) agent. NAC significantly reduced apoptosis, both NAC and ATRA induced an increase in CFU-GM, but NAC seemed to be particularly effective in the high risk (HR) MDS. NAC + ATRA conferred a significant advantage in terms of CFU-GM with respect to NAC and ATRA alone. Tumor Necrosis Factor-alpha (TNF-alpha) levels decreased after incubation with NAC in the MDS samples. This study shows that ineffective hemopoiesis in MDS could benefit from both NAC and ATRA, suggesting that anti-oxidant treatment may play a role in guaranteeing MDS cell survival, predisposing them towards differentiation.