IgG antibodies against pneumococcal surface protein A, family 1 (PspA1) and family 2 (PspA2), protein C (PspC), and protein Hic were investigated in 41 patients with invasive pneumococcal disease. Pre-existing antibody levels against the four pneumococcal proteins were not significantly different from those found in 40 patients with non-pneumococcal bacteremia or 80 healthy controls. However, during convalescense a strong immune response developed especially against PspA, and there was a high degree of cross-reactivity between PspA- and PspC-antibodies. Our findings on immunogenicity and cross-reactivity suggest that in a future pneumococcal protein based vaccine, only a limited number of proteins could be sufficient.