To better understand the viral aetiology of recurrent and prolonged illnesses, nasal secretions were prospectively collected from 285 infants at increased risk of developing asthma. Of these, 27 infants had recurrent (at least five) moderate-to-severe respiratory illnesses (MSIs). The viral aetiology of the 150 MSIs and 86 scheduled visits was analysed by molecular diagnostics. The demographic and clinical data were compared with infants who had 0-4 MSIs. Frequently ill infants had higher exposure to other children and more wheezing illnesses than less symptomatic children. Viruses were detected in 136 (91%) out of 150 MSIs, 14 (67%) out of 21 mild illnesses and 29 (45%) out of 65 asymptomatic visits. Human rhinovirus was the most common aetiological agent (61, 43 and 35% in MSIs, mild illnesses and asymptomatic visits, respectively). Mixed viral infections were generally associated with more severe illnesses (27, 0 and 5%, respectively). Among the 27 frequently ill infants, only eight (5.3%) out of 150 MSIs were prolonged (> or =2 weeks duration). Considering all samples, detection of the same virus strain > or =2 weeks apart was unusual (5.3% of all 244 positive findings). Human rhinovirus infections occur early, pervasively and repetitively in these high-risk infants. Infants with prolonged or recurrent respiratory illnesses most often have a series of infections rather than persistent infection with one virus strain.