Purpose: To explore the differences between exhausted CD8+ T cells in HCC patients with and without uremia.Methods: We enrolled 45 uremic patients who were recently diagnosed with HCC into the HCC & uremia cohort. We also enrolled similar patients with HCC but without uremia; this was the HCC only cohort. Lymphocytes were obtained from the two cohorts and exhausted CD8+ T cells, comprising PD-1+CD8+, TIM-3+CD8+, and LAG-3+CD8+ T cells, were sorted and expanded in vitro.Results: The proportions of PD-1+CD8+, TIM-3+CD8+, and LAG-3+CD8+ T cells after expansion were significantly higher in the HCC only cohort as compared to those in the HCC & uremia cohort. CD8+ T cells expressing PD-1, TIM-3, or LAG-3 showed increased tumor reactivity and release of IFN-γ in vitro; however, these cells demonstrated weaker anti-tumor activity in HCC & uremia patients than those in HCC patients without uremia. Among the expanded lymphocytes, only the decreased proportion of PD-1+CD8+ T cells correlated with the HCC & uremia cohort (OR: 2.731, p=0.009).Conclusions: Peripheral CD8+ T cells expressing PD-1, TIM-3, or LAG-3 from the HCC & uremia cohort were dysfunctional in vitro. Among these populations, PD-1+CD8+ T cells were the most predominant in HCC patients with uremia.