Background. Both antigen-dependent (immunologic) and non- antigen-dependent (nonimmunologic) factors have been implicated in long-term renal allograft loss. Differentiating between these two factors is important because prevention strategies differ. Methods. To isolate the importance of these 2 factors, we studied long-term actuarial graft survival in a cohort of adult kidney recipients who underwent transplants at a single institution between January 1, 1984 and October 31, 1998. Excluded were recipients with graft loss as a result of death with function, technical failure, primary nonfunction, and recurrent disease, leaving 1587 recipients (757 cadaver [CAD], 830 living donor [LD]) who would be at risk for graft loss secondary to both immunologic and nonimmunologic factors. These recipients were analyzed in the following 2 groups: those treated for a previous episode of acute rejection (AR) (Group 1; n=588; 328 CAD, 260 LD) and those with no AR (Group 2: n=999; 429 CAD, 570 LD). Actuarial graft survival and causes of graft loss were determined for each group. Presumably, graft loss in Group 1 would be caused by immunologic and nonimmunologic factors; graft loss in Group 2 would be caused primarily by nonimmunologic factors. Results. The 10-year graft survival rate (censored for death with function, technical failure, primary nonfunction, and recurrent disease) in Group 2 was 91%. In contrast, the 10-year graft survival rate in Group 1 was 45% (P<0.001 vs. Group 2). Causes of graft loss in Group 2 were chronic rejection in 1.8% (3.0% CAD, 0.9% LD), de novo disease, 0.4%; sepsis, 0.2%; discontinuation of immunosuppressive therapy, 0.3%; and unknown, 0.6%. In contrast, 23.8% (29.9% CAD, 16.2% LD) of recipients in Group I had graft loss caused by chronic rejection (P=0.001 vs. Group 2). Conclusions. This very low incidence of chronic rejection in recipients without previous AR suggests that immunologic factors are the main determinants of long-term kidney transplant outcome; nonimmunologic factors in isolation may have only a minimal impact on long-term graft survival.