The effect of the 23-valent pneumococcal polysaccharide vaccine (PPV) on the 7-valent conjugate (PCV) vaccine-induced priming was evaluated in 35 splenectomised beta-thalassemics [median (range) age: 30 (12-41) years] vaccinated with either PCV/PPV or two PCVs 1 month apart, followed by a PPV booster 12 months later. 28/35 had already received 1-3 PPVs in the past. Different schedules induced similar anamnestic responses; however priming for 3/5 serotypes induced by one or two PCVs, was inferior in subjects who had received > or =2 PPVs in the past when compared with 23 aged-matched PPV-naïve beta-thalassemics. One PPV following PCV does not affect PCV priming; multiple PPVs induce hyporesponsiveness for some serotypes in splenectomised subjects with beta-thalassemia.