Background: The knowledge of the immunological profile of patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) on haemodialysis (HD) is still limited. Aims: This study investigated the immune response profile in HCV patients with concomitant ESRD focusing on the influence of the renal disease on the phenotypic profile of peripheral blood lymphocytes. Methods: Immunophenotypic features of peripheral blood leucocytes were assessed by flow cytometry in two distinct groups: HCV patients with ESRD (CHC+ESRD, n = 16) and HCV patients with normal renal function (CHC, n = 20). Two control groups that were included were as follows: HCV negative blood donors (BD, n = 15) and HCV negative patients with ESRD (ESRD, n = 19). Results: Higher frequency of macrophage-like and pro-inflammatory monocytes along with enhanced frequency of CD3(-) CD16(-) CD56(+) , mainly CD56(dim) NK-cells, were the hallmark of CHC+ESRD patients. Lower frequency of B cells with significant decreased of B1 and CD23(+) B-cells were associated with ESRD, regardless the HCV infection. Although higher rates of activated CD4(+) and CD8(+) T cells were observed in the CHC and CHC+ESRD groups, the chemotaxis of T-cell subsets, based on their chemokine receptor expression, was affected by ESRD. Conclusions: Chronic hepatitis C patients with ESRD on HD exhibit distinctive phenotypic profile of circulating leucocytes. It may be implicated in the natural history of HCV infection in this particular group of patients and warrants further investigation.