BACKGROUND: The association between depression and immune response is not yet clear. The biological mechanisms by which depression alters the immune system is not yet understood. The purpose of this study was to investigate the longitudinal relationship between depressive symptoms and cellular immune response. METHODS: A cohort study with a baseline measurement and three annual health assessments was set up in a residential home for elderly people in Rome, Italy. A total of 166 residents aged 65 years and older, mean age 81 years, were interviewed and blood samples were collected at each annual assessment. Percentage changes in lymphocytes and T-cell subsets related to depressive symptoms were estimated over a period of 4 years, using regression models for repeated measurements. RESULTS: Elderly people with seven or more symptoms of depression, according to the Geriatric Depression Scale, had a lower percentage of CD4+DR+ T-cells over 4 years [beta = -20.2; 95% confidence interval (CI) = -33.0 to -4.9] and CD8+DR+ T-cells (beta = -26.9; 95% CI = -42.5 to -7.0) than elderly with less than seven symptoms of depression, after adjusting for confounding factors (sex, age, marital status, education, smoking habit, nutritional status, chronic diseases, disability and the use of benzodiazepines). CONCLUSION: The results of this study suggest an adverse effect of depressive symptoms on immune response. It remains to be determined whether these depression-associated immune changes are related to the onset or course of physical illness and the increased mortality observed in depressed old people.