These experiments compared the effect of a five-day course (days −1 to +3) of cyclosporine therapy coupled with pretransplant (day −1) administration of donor-specific antigen (whole blood or splenocytes) on either pancreatic or heart allograft survival in the Buffalo to Lewis rat donor-recipient combination. CsA therapy alone significantly (P<0.001) prolonged both heart (16.2±1.6 days) and pancreas (12.5±1.5 days) graft survival when compared with nonimmunosuppressed control heart and pancreas grafts (7.7±1.8 and 7.9±1.0 days, respectively). Pretransplant transfusion with either 2 ml of BUF whole blood or 2 × 108red cell-free splenocytes on day −1 also resulted in a significant (P<0.001) prolongation of heart survival (14.0±1.2 and 14.0±1.6 days, respectively) but did not improve pancreas allograft survival (9.4±1.5 and 8.5±1.0 days, respectively). Combination CsA and antigen therapy further improved heart graft survival to 26.5±6.1 days (whole blood) and 28.8±5.8 days (splenocytes) but did not improve pancreas graft survival over that of CsA therapy alone. Extension of CsA therapy by adding two additional 3-day cycles on days 10–12 and 17–19 further improved heart graft survival both after CsA alone (35.2±3.2 days) and after CsA coupled with whole-blood transfusion (45.3±8.6 days), but did not have a salutary effect on pancreas allograft survival. Portal vein administration of donor antigen was equally effective as systemic inoculation in prolonging heart graft survival when the splenocytes were given alone (11.6±1.7 days) or in combination with CsA (27.6±3.6 days). Conversely, pancreas allograft survival was not beneficially effected by portal antigen administration whether or not CsA was given. These data demonstrate the ability of pretransplant donor-specific antigen administration and short-term CsA therapy to significantly prolong rat heart allograft survival across a strong MHC histocompatibility barrier—but, surprisingly, they also demonstrate the failure of this regimen to have a salutary effect on pancreas allograft survival.