About 5%-10% of vaccinated individuals fail to produce a protective level of anti-hepatitis B surface antibody (anti-HBs) though hepatitis B vaccines show excellent immunogenicity in the general population. The percentage of humoral immunity failure to hepatitis B vaccination is about 30% in individuals infected with hepatitis C virus (HCV). However, mechanisms on the higher non-responsive rate in HCV patients are still unknown. Our study was conducted to describe the potential mechanisms of the Singling Lymphocytic Activation Molecule (SLAM) and SLAM-Associated Protein (SAP) between T cells and B cells borders during humoral immunity response. Based on anti-HBs Ab titers post immunization, we designated three groups: healthy controls (HC), vaccine responders in HCV-infected patients (VR), and vaccine non-responders in HCV-infected patients (VNR), respectively. Protein and mRNA expression levels of SAP and SLAM were determined among three groups at two time points, pre-vaccination and post-vaccination, respectively. For VR and HC, mRNA and protein expression levels of SAP and SLAM were elevated post-vaccination. However, these changes were not seen in VNR. Increased expression levels of SAP and SLAM may be associated with the development of a protective anti-HBs Ab response to hepatitis B vaccination. Therefore, modulation of SAP and SLAM may be considered as a strategy to improve vaccination for HCV-infected patients.