Abstract Background and Aims Immunosenescence, as a consequence of ageing or chronic inflammation, encompasses a spectrum of lymphocyte characteristics, including the presence or absence of certain lymphocyte surface molecules. Aim of the present study was to evaluate the immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosus (SLE), a chronic autoimmune disease and end stage renal disease (ESRD), a chronic inflammatory disorder. Method Certain lymphocyte surface molecules, including CD31, CD45RA, CCR7, CD28, CD57, for T, and IgD, CD27 for B lymphocytes, were analyzed by flow cytometry, and distinct naïve, active and senescent lymphocyte subtypes were determined, in SLE and ESRD patients. Results were compared to healthy controls (HC) of similar age, gender and nationality. Results Lymphopenia was significant in both SLE and ESRD patients, compared to HC, affecting B cells 75.4(14.4–520.8), 97(32–341) and 214(84–576)cells/μL, respectively, P < 0.0001, and CD4+ cells 651.2(71.1–1478.2), 713(234–1509) and 986(344–1591)cells/μL, respectively, P < 0.0001. The allocation of B cell subpopulations was remarkably different between SLE and ESRD patients, with the SLE showing a clear shift to senescent (IgD-CD27-) 11.75(2.3–74.2)% vs. 8.1 (1.7–35), and ESRD patients, to naïve subpopulations, compared to HC 69.9(1.1–92)% vs. 62 (4.5–86.9)%, P = 0.019. Instead, senescent subtypes of CD4+ lymphocytes, were reduced in SLE, compared to ESRD and HC, 3.2 (0.1–42.2)%, 6 (0.4–56.4)% and 3.5 (0.3–19.5)% for CD4+CD28null cells and 1.2 (0.1–23.9)%, 2.5 (0–51.9)% and 1.9 (0–17.9)%, for CD4+CD28-CD57+ cells. CD8+ lymphocyte subtypes presented a complete redistribution, in favor of CD8+CD45RA-CCR7+ (central memory), 53(1.8–92.4)%, 52.2(0.1–91.5)% and 23.4(0.1–92)%, respectively, and lowering the terminally differentiated populations (CD45RA+CCR7-), 2.8 (0–58.1)%, 7.8 (0.2–54.4)% and 12.8(0–71.6), respectively. CD8+CD28null cells were significantly reduced in SLE, compared to ESRD and HC, 31.9(1.1–87.2)%, 44.4(14–89.7)% vs. 34.5(6.4–72.3)%, respectively, P = 0.04. Conclusion Senescent phenotype of B lymphocytes predominated in SLE patients, while ESRD patients showed a completely different profile, with increased senescence involving mainly CD8+ lymphocytes.