Renal transplant recipients are known to develop higher incidence of malignancies compared to expected cancers in age-matched control population. We examined risk factors for malignancies among 380 Tunisian patients who underwent kidney transplantation between 1970 and 2004. Univariate analysis comparing survival curves with Log Rank test was performed.There were 33 “de novo” cancers occurring in 31 patients. The overall prevalence in our centre was 8,15 % with a mean follow-up of 93 months after transplantation. The mean age of recipients at the time of transplantation was 36 years. The mean age of transplanted patients who developed cancers at the time of diagnosis was 44 years with a sex-ratio of 1,6. The average time to appearance of tumors was 74 ± 10 months. Survival free of cancers in transplanted patients with functioning allograft was 96% at 5 years, 89% at 10 years, 81,5% at 15 years and 81,5% at 20 years. The most common malignancies were skin cancers which occurred in 10 patients followed by Kaposi sarcoma which affected 9 patients and lymphomas in 8 patients. Four kidney recipients developed an adenocarcinoma and two patients had brain tumors. In univariate analysis, recipient age, donor source, ciclosporine based therapy, HLA-A and HLA-DR mismatching were significant risk factors for cancer incidence. Multivariate analysis with Cox regression found all these factors as independent risk factors for cancers after renal transplantation. Only ciclosporine based immunosuppression was excluded by multivariate analysis. In agreement with other studies, age is a strong predictor of malignancies after renal transplantation. The adjusted relative risk attributable to age at transplantation (compared to age <35 years) was 3 (p:0,02) and to cadaveric donor, 2,6 (p:0,04). The adjusted relative risk attributable to HLA-A mismatching for two antigens as compared with no mismatching or mismatching for one HLA-A antigen was 5 (p:0,007). HLA-DR mismatching was also a strong predictor for malignancies. The adjusted relative risk due to HLADR mismatching for two antigens was 5 (p:0,006). Effort to reduce immunosuppression, regular check-up particularly for patients >=35 years of age at transplantation and optimal matching for HLA antigens between receiver and donor may help to reduce the risk of malignancies after kidney transplantation.