Risk factors for severe respiratory syncytial virus (RSV) infection were determined in 3 cohorts of adults during 2 consecutive winters (1999-2000 and 2000-2001) in Rochester, New York. Community-dwelling healthy persons > or =65 years old and persons >21 years old who had underlying symptomatic cardiopulmonary conditions were prospectively evaluated for RSV infection. Evidence of infection was also sought in persons who were > or =65 years old or had underlying cardiopulmonary disease and who were hospitalized with acute respiratory symptoms. Sixty-nine RSV infections were identified by culture, reverse-transcription polymerase chain reaction, or serologic testing in the prospective groups, and 61 were identified in the hospitalized group. The presence of underlying chronic pulmonary disease (odds ratio [OR], 3.97), functional disability (OR, 1.67/integer increase in Instruments of Activities of Daily Living score), and low serum neutralizing antibody titer (OR, 5.89) were each independently associated with increased risk of severe disease, defined as "hospitalization with RSV infection." These data suggest that the induction of neutralizing serum antibody with an RSV vaccine may potentially reduce disease severity in adult populations.