Allogeneic HSCT remains the only curative therapy for many patients(pts) with hematologic diseases. Studies have suggested that older pts experience greater toxicity from the intensive chemo-radiotherapy used in myeloablative conditioning regimens. As a consequence, many older pts are now offered non-myeloablative transplants (NMAT) for malignant conditions where a graft vs. tumor effect (GvT) is expected to provide the antitumor effect in place of the chemo-radiotherapy. Unfortunately, graft vs. host disease (GvHD) remains a common occurrence after conventional transplants, occurring more frequently in older pts and unrelated donor transplant recipients, resulting in significant morbidity and mortality. Furthermore, the efficacy of NMAT is limited by the disease status at time of transplant and by the susceptibility of the hematologic disease to a GvT effect. TCD of hematopoietic stem cell grafts offers an alternative to older pts, in particular those requiring unrelated donor transplants (URD), with the advantage of a reduced incidence of GvHD. From 1995–2005, 57 patients ≥55 yrs received myeloablative TCD transplants at our institution. The median age was 58.2 (range 55–69.2) yrs. Stem cell sources were TCD bone marrow, PBSC or both. Thirty-seven received transplants from related donors (RD), including two mismatched, and 20 received transplants from unrelated donors (URD), 9 of whom were mismatched. In addition to their advanced age, many of these pts were considered high risk based on the status of disease, HLA mismatch, and history of previous therapy. Twenty-three pts were considered “good risk” by disease status (CML-CP1, AML-CR1, CR2) and 34 pts were considered poor risk (>CML-CP1, >AML CR2, MDS, NHL, >ALL CR1, ABL.) BM was TCD by soybean agglutination followed by sheep red blood cell rosetting (E), and PBSCs by CD34+ selection and E-rosetting. Conditioning regimens included total body irradiation (TBI) in addition to thiotepa and cyclophosphamide, or thiotepa and fludarabine. The non-TBI preparative regimen consisted of busulphan, melphalan and fludarabine. Anti-thymocyte globulin was used as rejection prophylaxis for all TCD transplants until 2001 when it was eliminated from the TBI containing regimen for matched RD transplants. A total of 25 pts (15 matched RD and 10 URD, 6 of whom were mismatched) are alive following TCD transplants with a median follow up of 24 mos. for RDs and 12 for URDs. Of the survivors, 2/10 URD and 14/15 RD recipients received TBI containing regimens based on the triage system at our center. Three pts with CML-CP1, one with CML-acc and one with AML-CR1 showed evidence of minimal residual disease, received donor leukocyte infusions and subsequently achieved longterm continued CR. The incidence of post-transplant GvHD was low despite the high number of mismatched URD transplants - 1 Grade IV (RD), 2 Grade 3 and 1 Grade 1 (URD). The 100 day mortality was 15%. Overall and current disease free survival for ‘good risk’ patients based on disease status is 58% for RD and 60% for URD. Although longer follow up is necessary to confirm these results, the promising DFS rates in association with a low incidence of GvHD in this older and relatively high risk patient population support further investigation of myeloablative TCD HSCT in these patients.