It is well known that highly sensitized patients and/or high responders, even under CsA therapy, constitute a risk category for transplantation. Based on this evidence, in 1982, our group initiates a pilot study using total lymphoid irradiation (TLI) as a pre-transplant modulator of patient's immuno-response. TLI has been employed in 30 uremic, non diabetic, patients. During this experience the first protocol, characterized by pre-transplant TLI greater than 2,000 rads (13 pts.) and post-transplant conventional therapy, was abandoned because of the severe TLI side effects. In the second protocol TLI dose never exceeded 2,000 rads and CsA was given, at initial dose of 7-12 mg/Kg/day according to CsA blood through levels. The immunological monitoring was performed during TLI treatment and in the postoperative clinical course by cell markers profile determination and functional assays. The data obtained have demonstrated that TLI treatment causes a prolonged depression in CD4 positive cells, a predominant recovery of T suppressor population, a pronounced impairment of T functions and a development of specific unresponsiveness to donor antigens. Furthermore the TLI plus CsA protocol, showing an additive effect which steadily decreases patient immunoreactivity, a lack of side effects and a stable long term graft function seems to be a more useful method for transplantation in high-risk or in strongly immunoreactive patients.