Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3), respectively. CD4 levels were positively related to transplant duration (r = 0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P < 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.