Third renal transplants are historically associated with a poor prognosis. An analysis was undertaken to assess long-term outcomes of third grafts and identify variables associated with long-term graft survival. Fifty-six third grafts performed between 1974 and 2005 were compared to control groups of 1965 primary and 301 second grafts performed during the same period. Kaplan-Meier analysis showed a graft survival rate of 91%, 72% and 58% at 1, 5 and 10 years, respectively, for third transplants. Graft and patient survival of third grafts were similar to those of first and second transplants. Univariate analysis showed that HLA-A mismatch (P<0.01), absence of calcineurin inhibitor as part of the initial immuno-suppressive regimen (P=0.03), acute rejection (P=0.04) and transplantation prior to 1990 (P=0.04) were associated with a poor third graft survival. Multivariate analysis indicated that 1 year serum creatinine (HR=1.02, P=0.001), 1 year proteinuria (HR=1.84, P=0.01), absence of calcineurin inhibitor (HR=10.6, P=0.01) and complete HLA-A match (HR=0.13, P=0.03) were independently associated with graft loss. Although third graft recipients have a range of risk factors previously associated with poor patient and graft outcome, that remain difficult to delineate in a retrospective analysis due to the possible selection of the third transplant candidates, these results suggest that third graft and patient survival rates could be similar to those of first and second transplants.