Nasopharyngeal colonization with Moraxella catarrhalis was evaluated in a large cohort of infants followed prospectively from birth to 2 years of age; 120 children were examined at 13 routine visits. Of these, 66% became colonized with M. catarrhalis by 1 year and 77.5% by 2 years. Nasopharyngeal colonization with M. catarrhalis increased from 27.0% during healthy visits to 62.7% during visits due to otitis media (P < .001). Otitis-prone children were colonized at 44.4% of all visits compared with 16.7% for children who did not have otitis media (P < .001). DNA from 112 strains of M. catarrhalis from 34 children were evaluated; 106 were successfully digested with restriction enzymes and demonstrated a great degree of heterogeneity. Children tended to acquire and eliminate a number of different strains. Intrafamilial spread of the same strain of M. catarrhalis was frequent. These data suggest that nasopharyngeal colonization with M. catarrhalis is common throughout infancy. A high rate of colonization is associated with an increased risk of otitis media.