In a pilot study, we carried out Haploidentical transplantation for 10 patients with severe aplastic anemia (SAA) using peripheral blood stem cell (PBSC) graft and posttransplantation cyclophosphamide (PTCY). The conditioning comprised of Fludarabine 150 mg/m2, CY 30 mg/kg, horse ATG 45 mg/kg and Melphalan 120 mg/m2, followed by PTCY 50 mg /kg on D+3, +4 and cyclosporine and mycophenolate from D + 5. Prompt engraftment was followed by early alloreactivity, resulting in transplant-related mortality in 4 of the first 5 patients, all with NK Ligand mismatched donors. In the subsequent 5 patients, Sirolimus was introduced from Day -7 to maintain a trough level of 8-14 ng/ml on the day of transplant and was continued for 12 months post-transplant, with a reduced trough level for cyclosporine. All 5 patients had prompt engraftment with 78-100% donor chimerism and mild chronic GVHD in one patient only. The only significant toxicity observed in these patients was Sirolimus associated acneform lesions. Analysis of Regulatory T cells at 45 days posttransplant was 0.09 ± 0.13% in the first 3/5 patients compared to 2.6 ± 0.77% in those receiving Sirolimus (p=0.001). Our study demonstrates that NK cell ligand mismatched donors are associated with early alloreactivity following Haploidentical PBSC transplantation for SAA but addition of Sirolimus to PTCY improves tolerance and outcome.