BACKGROUND: Respiratory syncytial virus (RSV) is recognized as a serious pathogen in people with chronic cardiopulmonary conditions. Immunoprophylaxis might be considered for adults at high-risk for frequent and severe RSV infection. Thus, we studied the incidence of RSV-related medically attended acute respiratory illness (MARI) in adults with severe chronic obstructive pulmonary disease (COPD) and/or congestive heart failure (CHF). METHODS: Subjects >/=50 years of age with Gold Class III/IV COPD and/or American Heart Association class III/IV CHF and exposure to children >/=once per month were recruited. Subjects were evaluated over 1.5 to 2.5 years for RSV-associated MARI, defined as polymerase chain reaction (PCR) and/or seroresponse. RESULTS: Four hundred forty-five subjects were enrolled between October 2011 and May 2012. Overall, 99 RSV infections were documented by PCR or serology for a cumulative incidence of 22.2%. Of these, 42 (9.4%) subjects had protocol-specified RSV-MARI for an incidence of 4.68/100 patient-seasons. All-cause MARI was common (63.85/100 patient-seasons) with rhinovirus most commonly identified. CONCLUSION: RSV infection was common in adults with severe COPD and/or advanced CHF. Given the severity of underlying cardiopulmonary diseases in the study population, most illnesses were surprisingly mild. Thus, active immunization rather than passive immunoprophylaxis with monoclonal antibodies may be a more cost-effective strategy.