Non-myeloablative allogeneic SCT is associated with AGVHD rates similar to conventional allografting. Animal models have consistently shown engraftment across MHC barriers when anti-T cell antibodies are combined with low doses of thymic irradiation or TBI. In December 2001, we initiated a prospective study evaluating a novel conditioning regimen for allogeneic SCT, combining Thymoglobulin 2.5 mg/kg/day given from day -4 to d -1 with 2-Gy TBI on d 0, followed by G-CSF mobilized hematopoeitic stem cells from matched sibling (MSD) or unrelated donors (URD). GVHD prophylaxis consisted of tacrolimus (d-4 to 30, tapered thereafter) and methotrexate (5mg/m2; d 1, 3 & 6). Sixteen patients (7 female) have been transplanted; 5 each with MM & NHL, 3 with CLL/SLL, 1 each with WM/MDS, CMPD & MDS-AML. A median of 2 prior therapies had been given (range 1–5; 7 patients had prior autografts); 3 patients were in CR, 8 had persistent disease and 5 were in untreated relapse at transplant. Median age was 57 years (range 70-43); 11 received grafts from MSD and 5 from URD (3 BMT). Median CD34+ cell dose infused was 5x106 /KG and CD3+ cell dose 3.4x108 /KG. The regimen was well tolerated with only 5 patients developing reversible grade II-III non-hematopoeitic toxicities in the peritransplant period. Despite 14 patients having major or minor (8) ABO incompatibility, only one patient developed allo-immune hemolysis requiring blood transfusions. Fifteen patients (93%) had hematopoeitic reconstitution by d30 with a median 94% (range 53–100) donor derived hematopoiesis by PCR for STR loci in blood; 95% at d60 (68–100; n=13), 95% at d90 (25–100; n=13) and 95% around d180 (1–100; n=11). WBC subset chimerism analysis in the first 3 months showed neutrophils (96, 95, 98 % donor derived) correlating with monocytes (95, 96, 100); total T cells (85, 86, 71) matched helper T cells (93, 86, 85) and cytotoxic T cells (82, 83, 80). The lower proportion of donor derived lymphocytes was reflective of poor lymphoid recovery related to the ATG based conditioning, with median absolute lymphocyte count at 3 months being 500/μL (100-900). As of August 2004, with a median follow-up of 18 mo (1–31 mo), 12/16 (75%) patients are alive; 38% are event-free (DLI, relapse or death). Day-100 and 1-year survival are 86 & 76% respectively. 10/12 (83%) surviving patients are without disease progression (7 in CR). These patients are 92–100% donor chimeric in blood (5 URD: 4 with prior autografts, 5 MSD: 2 with autografts). Despite withdrawal of immunosuppression by d100 in 11/13 evaluable patients only two patients (12%) receiving URD-PBSCT developed GII-III AGVHD (steroid responsive). Limited chronic GVHD developed in 4 patients undergoing URD-SCT. Three patients (19%; all gender matched MSD) developed graft rejection in the context of relapsing disease; 4 have died with disease progression. Nine patients (all MSD) received donor cell reinfusion (4 with reconditioning) at median d 121 (66–217); 4 for mixed chimerism alone and 5 with persistent disease. Five patients had increased donor chimerism following DLI. In conclusion, in selected patients this approach leads to rapid donor engraftment with minimal acute toxicities and GVHD despite early withdrawal of immunosuppression, especially in patients with a prior autograft or in those being transplanted using an URD.