Rationale: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses. Objectives: To identify factors that influence the severity of HRV illnesses. Methods: HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI). Measurements and Main Results: Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5-to 10-fold more likely to cause MSI in the winter months (P , 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P ¼ 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%. Conclusions: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.Keywords: rhinovirus; severe illness; species; type; seasonality Human rhinoviruses (HRVs) are the most prevalent human respiratory viruses. Annually, they infect billions of people and are responsible for at least one-half of all acute upper respiratory illnesses (common colds), the most common illness of humans (1-3). In addition to common colds, infections with HRV result in a wide range of other clinical outcomes ranging from asymptomatic infection to severe lower respiratory illnesses, such as bronchiolitis, pneumonia, and exacerbations of asthma (1, 4-7). It is likely that host, viral, and environmental factors contribute to the severity of illness caused by HRV infection. Indeed, more severe HRV infections are associated with phenotypic characteristics such as extremes in age; chronic respiratory diseases such as asthma; reduced interferon responses in the blood and airway; and, in early life, male sex and reduced lung function (4,8). Little is known about viral and environmental determinants of illness severity.HRVs are a large group of genetically diverse RNA viruses and are classified phylogenetically into three species (A, B, and C). The 100 classical serotypes are found within species A and B, and approximately 50 newly identified types are HRV-Cs (5, 9-15). This tremendous genetic diversity represents a major obstacle toward developing both antivirals and vaccines for HRV, and iden...