OBJECTIVES: We assessed the immunological response of hospitalized adult patients with rhinovirus infection, including critically-ill patients. METHODS: The differential white blood cell (WBC) count and the levels of 29 plasma cytokines/chemokines were compared between 50 adult hospitalized patients with rhinovirus infection and 100 age-matched controls with influenza virus infection. RESULTS: The demographics and comorbidities were similar between rhinovirus and influenza patients, but severe disease was more common for the rhinovirus cohort. Rhinovirus patients had significantly higher WBC counts than influenza patients, especially for eosinophil (P = 3.1 x 10(-8)). The level of the TH2 cytokine IL-5 was significantly higher among rhinovirus patients, while the levels of 9 other cytokines/chemokines were significantly lower among rhinovirus patients. The levels of CXCL-10 (IP-10), CCL-2 (MCP-1), IFN-alpha2, IFN-gamma, IL-10, and IL-15 remained significantly lower among rhinovirus patients after correction for multiple comparisons. Notably, CXCL-10 had the highest area under the receiver operating characteristic curve (AUC) in differentiating rhinovirus from influenza patients (AUC, 0.918). In the patient subgroup without asthma, the difference in the WBC count and cytokine/chemokine levels between rhinovirus and influenza patients remained statistically significant. CONCLUSIONS: Rhinovirus infection was characterized by a prominent TH2 response, even in patients without asthma. CXCL-10 (IP-10) is a potential biomarker in differentiating rhinovirus from influenza infection.