OBJECTIVES: Patient-reported outcomes such as health-related quality of life (HRQL) are a frequent endpoint used in studies of Major Depressive Disorder (MDD), but little is known if results of these scales conducted during randomized clinical trials (RCT's) accurately reflect patients’ perceptions of the “real world”. METHODS: An observational study and a randomized double blind clinical trial with similar design, inclusion and exclusion criteria and schedule of visits were used. These two eight-week studies evaluated primary care MDD patients according to the DSM-IV. Patients were asked to fill in the EuroQoL and the Quality of Life in Depression Scale (QLDS) at baseline and eight weeks later, while physicians rated the severity of depression using the Montgomery-Åsberg Depression Rating Scale (MADRS). Baseline characteristics were compared to reveal potential confounders, and adjusted mean HRQL change from baseline were compared using analysis of covariance. RESULTS: A total of 288 RCT patients and 244 patients from the observational study were compared. At baseline, patients from the observational study were statistically significantly younger (44.0 ± 14.5 vs. 48.0 ± 14.0, p=0.002) and more severely impaired (MADRS: 33.0 ± 7.4 vs. 28.9 ± 5.2, p<0.001) than RCT patients. Baseline EuroQoL scores were significantly higher for RCT patients (0.50 ± 0.28 vs. 0.30 ± 0.25, p<0.001), indicating a better HRQL, while QLDS scores were not significantly different (18.0 ± 4.4 vs. 17.9 ± 5.4, p=0.69). Both adjusted mean HRQL change from baseline scores were significantly lower for RCT patients than for patients from the observational study: -5.8 ± 0.3 vs. -7.6 ± 0.3, p<0.001 and 0.31 ± 0.11 vs. 0.38 ± 0.09, p<0.05 for QLDS and EuroQoL, respectively. CONCLUSIONS: Improvement in HRQL scores during acute treatment of MDD seems to indicate that their results may be underestimated in RCT's.