The rational of this study we intended to investigate whether the peripheral blood immunological/virological biomarkers were associated with distinct patterns of sleeping quality in patients with chronic hepatitis C-(HCV). Distinct well-established indexes/scores were used to categorize the sleeping quality of HCV patients, including the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale and Fatigue Severity Scores. Our findings demonstrated that HCV patients classified as ‘good sleeper’ displayed an enhanced frequency of circulating CD8+ T cells, lower frequency of activated (CD69+) neutrophils and eosinophils but enhanced frequency of activated lymphocytes besides lower seric levels of IL-4/IL-8/IL-10 but higher levels of IL-12, besides lower HCV virus load and lower anti-HCV IgG levels. In contrast, HCV patients classified as ‘poor sleeper’ displayed enhanced levels of activated neutrophils and eosinophils but lower frequency of activated lymphocytes, higher seric levels of IL-6/TNF-α/IL-10 but lower levels of IL-12 besides higher HCV virus load and increased anti-HCV IgG levels. Positive correlation was further confirmed by the relationship between the leucocyte activation status, the cytokine levels, the HCV viral load and the anti-HCV IgG reactivity with the PSQI indexes. Analysis of cytokine signature curves demonstrated that lower frequency of IL-10 was observed in HCV patients classified as ‘good sleepers’, whereas enhanced frequency of IL-6 was found HCV patients classified as ‘poor sleepers’. In conclusion, our data suggest that immunological biomarkers (leucocytes activation status and seric cytokines levels) are likely to be associated with sleeping quality patterns in HCV patients, suggesting their putative use for clinical monitoring purposes.