Exacerbations of multiple sclerosis (MS) are triggered by exogenous events, the best documented being viral upper respiratory infections (URIs), which can stimulate secretion of cytokines such as interferon-gamma (IFN-gamma) by immune cells. In conjunction with a recent clinical trial of systemic interferon-beta (IFN-beta) in relapsing-remitting MS, we studied the occurrence of viral infections and their correlation with MS attacks. Thirty patients kept daily logs, noting URI symptoms in themselves, family members, and co-workers. Patients were examined every 3 months, or whenever an attack of MS occurred, and were tested for antibodies to common upper respiratory pathogens. A strong correlation was found between MS attacks and URIs. There were 168 URIs in 2,792 patient-weeks, including 996 weeks at risk (the interval beginning 1 week before and ending 5 weeks after onset of URI symptoms) and 1,796 weeks not at risk. Nearly two-thirds of attacks occurred in periods at risk. Attack rates were 2.92 per year in weeks at risk compared to 1.16 per year in weeks not at risk, a significant difference (p < 0.001). High-dose interferon reduced the frequency of MS attacks, but had no effect on the number of URIs. Although a specific virus could not be incriminated, we concluded that URIs of presumed viral origin are an important trigger of MS attacks, and that treatment with IFN-beta reduces the attack rate, but not by preventing URIs. Rather, it may modulate responses to viral infection that would otherwise lead to immune activation and clinical symptoms.