OBJECTIVE The current study investigated whether differences existed in health-related quality of life between individuals who self-identified as having childhood-onset asthma and individuals without a chronic illness. Additionally, the relationship between perceived illness intrusiveness and illness uncertainty to health-related quality of life was explored. METHODS College undergraduates at least 18 years of age who self-identified as having childhood asthma were randomly matched by age and gender to healthy control participants. Participants completed a demographic form, the Mishel Uncertainty in Illness Scale-Community Form, the Illness Intrusiveness Scale, and the SF-36 Health Survey, a measure of health-related quality of life. RESULTS Participants with asthma had significantly lower scores on the total and mental health-related quality of life scales than did healthy control subjects. There were no significant differences between self-identified participants with asthma and matched healthy control subjects on physical health-related quality of life scales. Illness intrusiveness was not related to either the physical (e.g., physical functioning, general health) or mental health-related quality of life. Higher levels of illness uncertainty were significantly related to higher levels of mental health-related quality of life (e.g., vitality, mental health). In addition, participants with asthma scored significantly lower than healthy controls on the social functioning and role-emotional subscales. CONCLUSIONS The current study adds to the extant literature by examining the relationships between illness intrusiveness, illness uncertainty, and health-related quality of life among a young adult population. College students with asthma appear to be at risk for diminished quality of life compared to a healthy comparison group. Further examination of various domains of health-related quality of life among older adolescents and young adults with childhood asthma is needed.