We investigated the trend of the carriage of drug-resistant Streptococcus pneumoniae in nasopharynx of children. The 202 isolates from pediatric outpatients and their previous antibiotic use was investigated from 2004 to 2006. The total rate of patients medicated with antibiotics was 47.5%, a 6.9% decrease compared with our previous study performed from 2001 to 2003. There were 56 (27.7%) penicillin-susceptible, 83 (41.1%) penicillin-intermediate, and 63 (31.2%) penicillin-resistant strains by the susceptibility breakpoints used during the previous study period. There were 196 (97%) susceptible, 5 (2.5%) intermediate, and 1 (0.5%) resistant strains by breakpoints in this study, which were introduced in 2008 by the Clinical Laboratory and Standards Institute. The rate of strains with a single altered pbp gene was 21.8% (44), with 2 altered pbp genes was 21.8% (31), and with 3 altered pbp genes was 53.5% (108). The total rate of strains with altered pbp gene(s) was 90.1% (183). We found the emergence of strains with pbp1a and 2b and the higher rate of strains with pbp2x. There was obvious association between amoxicillin use and the carriage of altered pbp gene(s). These results might suggest that amoxicillin was not a safe alternative to prevent the emergence of resistant strains. We need to reassess a beneficial approach for the treatment of pediatric outpatients.