Understanding the virus‐host interactions that lead to approximately 20% of patients with acute Hepatitis C Virus (HCV) infection to viral clearance is probably a key towards the development of more effective treatment and prevention strategies. Acute hepatitis C infection is usually asymptomatic and therefore rarely diagnosed. Nevertheless, HCV nucleic acid testing carried out on all blood donations detects donors who have resolved their HCV infection after seroconversion. Here we have used SELDI‐TOF‐MS technology to compare, at a proteomic level, plasma samples respectively from donors with HCV clearance, from donors with chronic HCV infection and from unexposed healthy donors (n = 15 per group). A candidate marker of about 9.4 kDa was detected as differentially expressed in the three groups. After purification we identified by nanoLC‐Q‐TOF‐MS/MS this candidate marker as Apolipoprotein C‐III (ApoC‐III). The identification was confirmed by western blot analysis. Levels of ApoC‐III were then determined in the 45 plasma samples by immunoturbidimetric assay. ApoC‐III was found to be higher in donors who had resolved their HCV infection than in donors with chronic infection, results which were consistent with SELDI‐TOF‐MS data. ApoC‐III is the first reported candidate biomarker in plasma associated with the spontaneous resolution of HCV infection.