Tacrolimus is increasingly used as a baseline immunosuppressant after renal transplantation. This multicentre study assessed health-related quality of life and symptom experience in renal transplant patients on tacrolimus-based therapy, using the SF-36 and Euroqol 5 dimensions (EQ-5D) and the 'modified transplant symptom occurrence and symptom distress scale', respectively. Symptoms of depression were assessed with the short form of the Beck Depression Inventory and physical activity with the Baecke questionnaire. Overall, 350 patients with a median post-transplant status of 16.7 months were enrolled. Results revealed that patients experienced lower SF-36 scores than the general population, except in terms of bodily pain. Univariate and multivariate analyses demonstrated that a higher degree of depressive symptoms and female gender were consistently related to a health status perceived as being worse and a higher rate of symptom experience. These findings are in accordance with previous quality-of-life reports that assessed patients under various immunosuppressive therapies. Therefore, interventions, including the screening and treatment for depression and the addressing of gender-specific issues, can enhance quality of life.