BACKGROUND: This study aims to identify factors associated with health related quality of life (HRQOL) through a comprehensive analysis of sociodemographic and clinical variables among a representative sample size of renal transplant recipients (RTR) in France. METHODS: A cross-sectional multicenter study was carried out in 2008. All RTR over 18 years old with a functioning graft for at least one year were included. Data included socio-demographic, health status, and treatment characteristics. To evaluate HRQOL, the Short Form-36 Health Survey (SF-36) and a HRQOL instrument for RTR (ReTransQol) were administered. Multivariate linear regression models were performed. RESULTS: A total of 1061 RTR were included, with a return rate of 72.5%. The variance explained in regression models of SF-36 ranges from 20% to 40% and from 9% to 33% for ReTransQol. CONCLUSIONS: The originality of our study's findings was that novel variables, particularly treatment side effects and unemployment, have a negative effect on quality of life of RTR. The French Biomedicine Agency and the National Health Institute for Public Health Surveillance conduct specific actions for professional reintegration and therapeutic education programs in the national plan to improve the HRQOL of people living with chronic diseases.