Viral upper respiratory infection is one of the most common diagnoses made in primary care offices. Although symptoms resolve within 1 week for many patients, a percentage develops rhinosinusitis, and many of these patients are treated with antibiotics. We have developed a model of viral rhinosinusitis using intranasal inoculation of reovirus into mice that were then killed on postinoculation days 2, 4, 7, 10, 14, or 21 and heads were embedded in paraffin for histological and immunohistochemical analyses. Reovirus-like immunoreactivity was noted in the septa and paranasal sinus mucosa in mice as early as day 2, with peak intensity seen on day 4, and scant staining seen on day 7. Complete absence of viral staining was seen by day 10, which corresponded with increased intracellular adhesion molecule 1 immunostaining in the nose. By day 10, a large mucosal influx of B cells was observed, with a moderate influx of macrophages and smaller influx of T cells. By day 14, there was a peak in the number of B cells with a corresponding, but less pronounced peak in T cells, while macrophages began to decline at this point. By day 21, the panel of immune markers returned to near normal levels. The results of this study suggest that the immune system continues to produce a response as long as 2 weeks after clearance of viral antigens. One proposed mechanism for this phenomenon is that local factors such as cytokines are released continually after infection, even in the absence of persistent viruses or bacteria.