O142* Aims: We have suggested that the heavy conventional immunosuppression used for organ transplantation subverts the seminal tolerogenic mechanism of clonal exhaustion-deletion and thereby contributes to long-term drug dependence. Methods: This self-defeating effect was avoided in 175 adult kidney recipients (mean 49.9 ± 14.3 years) treated between July 2001 and September 2003; 43 (24.6%) had adjunct donor bone marrow cell infusion. Two therapeutic principles were applied: (1.) recipient pretreatment (with 5 mgm/kg Thymoglobulin); (2.) minimal post-transplant immunosuppression (with tacrolimus monotherapy, initial target trough 10 ng/ml). Twenty-five (14.2%) patients were undergoing retransplantation, and 34 (19.4%) had a PRA >20%. Mean HLA mismatches were 3.1 ± 1.7. One hundred kidneys (57%) were cadaveric (mean cold ischemia 25.6 ± .7 hours) and 75 (43%) were live donated. Mean donor age was 39.9 ± 6.3 years (range 1-66). Post-transplant doses of tacrolimus were spaced to every other day or longer at various times after four months. Results: With a mean follow up of 16.9 ± 7.1 months, the actuarial one and two patient survival is 97% and 95% with graft survival of 91% and 84%. Mean current serum creatinine is 1.95 ± 1.14 mg/dl. The incidence of preweaning acute clinical rejection was 34.9% (6.3% steroid resistant). Weaning was attempted in 149 cases (85.1%) and interrupted by rejection in 45 (30.2%). Currently, 111 (63.4%) patients are at various stages of weaning: 25 (14.2%) every other day, 44 (25.1%) three times a week, 28 (16%) two times a week, and 14 (8%) once a week. Ten percent of patients had asymptomatic CMV infection and there was one BK infection, but the incidence of CMV disease, diabetes, and PTLD was 0%. Conclusions: With significant numbers of highly weaned patients beyond the two-year mark, we continue to apply this strategy of immunosuppression, which is neither drug nor organ specific.