In New York State during winter 2004, there was a high incidence of influenza-like illness that tested negative both for influenza virus, by molecular methods, and for other respiratory viruses, by virus culture. Concern that a novel pathogen might be implicated led us to implement a new multiplex diagnostic tool. MassTag polymerase chain reaction resolved 26 of 79 previously negative samples, revealing the presence of rhinoviruses in a large proportion of samples, half of which belonged to a previously uncharacterized genetic clade. In some instances, knowledge of the detected viral and/or bacterial (co)infection could have altered clinical management