Health-related quality of life scales such as the Asthma Quality of Life Questionnaire and the Medical Outcomes Study Short-form General Health Survey SF-36 have become important measures of health status in clinical asthma trials. The discriminative properties of these scales, however, have not been extensively evaluated and compared. The purposes of this study were to assess and compare scale and discriminative properties of the Asthma Quality of Life Questionnaire (AQLQ) and the SF-36 in a group of patients with moderate asthma using a patient-rated global measure of disease activity as the criterion variable. Patients were interviewed in-person with a series of questionnaires including the AQLQ and the SF-36, and were also asked the global question "How active is your asthma now?" with possible responses of "extremely," "very," "moderately," "mildly" or "not active." Discriminative properties were determined using receiver operating characteristic (ROC) curves with responses to the global question as the criterion variable and mean domain scale scores as the independent variables. Relative validities for the AQLQ and SF-36 domains were also compared. A total of 230 patients, mean age of 41 years, were enrolled. Scores were lower and ranges were narrower for the AQLQ compared to the SF-36. In general, the AQLQ and the SF-36 were highly correlated, with r = 0.69 for the AQLQ overall score and the SF-36 Physical Component Summary (PCS) score. According to ROC analyses, both scales had excellent discriminative properties; however the area under the ROC curve was higher for the AQLQ overall score (0.81) than for the PCS (0.75). When ranked according to ROC area, the symptoms domain (0.83) had the greatest area under the ROC curve, followed by the emotional (0.76) and activities (0.76) domains of the AQLQ. However, in some cases, the area under the curve was less for an AQLQ domain (for example, 0.71 for the environmental domain) than for SF-36 domains (for example, 0.75 for the role physical, and 0.75 for the social domain). Similarly, the AQLQ overall had a higher relative validity (5.2) compared to the PCS (2.2), and the symptoms domain of the AQLQ had the highest relative validity (6.0). Thus, both the Asthma Quality of Life Questionnaire and the SF-36 were able to characterize patients with moderate asthma in our cross-sectional study. In addition, both scales had strong discriminative properties when assessed with a global patient rating of current disease activity.