The relative effects of risk factors on the prevalence of resistant pneumococcal clones are hard to determine. Our aim was to evaluate the effect of risk factors on the prevalence of resistant pneumococci in Iceland in 2003 and compare these data with results of identical studies performed in 1993 and 1998. A randomized sample of 1,107 children was chosen from all 2,532 children 1 to 6 years old living in four communities. Pneumococci were carried by 64% of the 824 children enrolled and 9.5% were penicillin nonsusceptible (PNSP), as opposed to 8.1% (1998) and 8.5% (1993), and multiresistant strains of serotype 6B were 2.5% compared to 7.5% and 7.7% (p < 0.001). Antimicrobial use had declined in 10 years from 1.5 to 1.0 courses/child per year. The only significant risk factor for carriage of PNSP and erythromycin-resistant pneumococci was antimicrobial consumption. The multiresistant type 6B strains disappeared from the areas with the lowest antimicrobial use but maintained unchanged prevalence in the area with the highest use. The number of erythromycin- resistant, penicillin-susceptible strains of all pneumococci (37/475, 7.8%) increased significantly from the previous studies (7/353, 2.0%, 1998, and 2/390, 0.5%, 1993). This observation is associated with increased use of macrolides, especially azithromycin, in one of the study areas. Spread of novel resistant clones appears to be the main reason for rapid and significant changes in pneumococcal resistance rates. The choice of antimicrobial class appears to influence the selective environment favoring particular resistant clones.