An important goal of rehabilitation and treatment after spinal cord injury (SCI) is to improve function and enhance health-related quality of life (HRQoL). However, previous assessments are limited by use of HRQoL instruments not specific to SCI. Although respiratory dysfunction is common in SCI, it has not been possible to assess the association of comorbid medical conditions, including respiratory symptoms and pulmonary function, to HRQoL. Therefore, we assessed whether these factors were associated with HRQoL in SCI using an SCI-specific HRQoL questionnaire. In our cross-sectional study, 356 participants >or=1 yr post-SCI completed a 23-item SCI-specific HRQoL questionnaire and a detailed health questionnaire, and underwent pulmonary function testing and a neurological exam at VA Boston between 1998 and June 2003. In a multivariate regression model, age, employment status, motor level and completeness of injury, and ambulatory mode (use of hand-propelled or motorized wheelchair, use of crutches or canes, or walking independently) were independently associated with HRQoL. After adjusting for these factors, chronic cough, chronic phlegm, persistent wheeze, dyspnea with activities of daily living, and lower forced expiratory volume in 1 sec and forced vital capacity were each associated with a lower HRQoL. These results provide evidence for the clinical validity of our SCI-specific HRQoL instrument. We also identify potentially modifiable factors that, if addressed, may lead to HRQoL improvement in SCI.