Coexisting diseases may have unforeseen yet clinically significant effects on patients' well-being. Both generic and disease-specific measures are frequently used to assess health-related quality of life (QOL). The present study assessed the effects of comorbidity on the results of QOL measures through an analysis of longitudinal data from 3 double-masked, randomized, placebo-controlled clinical trials dealing with heartburn, asthma, and ulcer. Patients were assigned to subgroups by comorbidity status: those with no comorbid diseases and those whose principal disease was heartburn, asthma, or ulcer and whose comorbid condition was chronic obstructive pulmonary disease, asthma, or chronic bronchitis; hypertension; migraine, coronary artery disease, or varicose veins; chronic gastrointestinal conditions; arthritis or back pain; diabetes; or depression. Multivariate analysis of covariance was used to test the study hypotheses. The study results suggest that comorbid conditions significantly and extensively affect patients' scores on generic QOL measures and estimation of treatment effect, whereas their influence on disease-specific QOL scores and estimation of treatment effect is considerably smaller. Further, the most important comorbidities in the 3 trial populations were arthritis or back pain and depression, which respectively accounted for 17% and 5% of the patient population. These findings have significant practical implications for the estimation of true treatment effects, control of comorbidity effects, and design of QOL trials.