Chronic rejection remains the single most important cause of renal allograft loss after the first year post-transplant. We performed a matched case control study within our cohort of 471 renal allograft recipients, comparing 66 patients with histologically proven chronic rejection with 66 controls. Analysis of immunological (transfusion, sensitisation, HLA matching, number of transplantation, number of acute rejections (AR), immunosuppression) and non-immunological (donors and recipients age and sex, CMV disease, post-transplant acute tubular necrosis, cold ischemia) factors which could predict the occurrence of chronic rejection (CR) was performed, using Wilcoxon rank test, Mac Nemar test and Cox model. Univariate analysis showed that potential risk factors for CR are: donor age > 45 years (p = 0.05), recipient age < 40 years (p = 0.008), CMV disease (p = 0.03), number of acute rejection episodes (p = 0.009), retransplantation (p = 0.002). Multivariate analysis showed that only the following factors significantly increased the risk of CR: AR episodes (p = 0.01) with an odds-ratio at 3.5 (95% CI = 1.3-3.9) for the second acute rejection episode and at 6.5 (95% CI = 1.5-29.4) for the third acute rejection episode, donor age > 45 years (p = 0.03) with an odds-ratio at 3.5 (95% CI = 1.1-10.6). Our data suggest that better matching at donor recipient age and more potent immunosuppressive protocols resulting in no acute rejection may improve the long term graft survival. They also show that the use of old donors (> 45 years), as a response to organ shortage is detrimental for long term renal function.