Abstract Evaluation of specific antibody (Ab) response to polysaccharide antigens is essential for diagnosis of primary immunodeficiencies. We assessed the specific Ab responses to the pneumococcal-polysaccharide (PPV) and to Salmonella typhi-polysaccharide (TyphimVi) vaccines in a prospective study (EMPATHY) in patients with common variable immunodeficiency (CVID-Group, n = 22), hypogammaglobulinemia (HYPOG-Group; n = 27) and healthy controls (HC-Group; n = 16). Specific Ab concentrations in response to PPV and to TyphimVi vaccines were measured by ELISA (The Binding Site, UK), defining 3-fold increase as normal response (Ratio:3x). The RatioTyphimVi:3x was significantly greater in HC than in CVID-Group (p < 0.0001), but not than HYPOG-Group (p = 0.138). However, the RatioPPV:3x showed no significant differences among the three groups. By ROC analysis, TyphimVi better differentiated HC from CVID (AUC:0.893, IC95%: 0.791-0.996, p < 0.0001) than PPV. Our results suggest that the use of specific Ab response to TyphimVi could represent a complementary assay for the diagnosis of anti-polysaccharide Ab production deficiency in patients with CVID.