OBJECTIVES: Major depressive episodes (MDE) and anxiety are associated with decreased health-related quality of life (HRQL). The EQ-5D assesses five domains, including the single domain of Anxiety/Depression. Thus, the EQ-5D may be limited in differentiating among subjects with either or both of MDE and anxiety disorders. Our objective was to determine the ability of the EQ-5D to differentiate among persons with MDE or anxiety alone or in combination, compared with neither. METHODS: Data were collected in 2003 as part of the Alberta Mental Health Survey and were obtained through random digit dialing and computer assisted telephone interviews. MDE and anxiety were defined by DSM-IV using the Mini International Neuropsychiatric Interview. HRQL was measured with the EQ-5D; responses on the Anxiety/Depression domain were dichotomized to 1) no problem, or 2) moderate/extreme problems. Descriptive and multivariate analyses were used to examine associations between EQ-5D scores and mental health diagnoses. RESULTS: The average age of the sample (n=5383) was 40.8 (12.1) years, 61% were female. The prevalence for diagnoses (and proportion within each group reporting problems on the Anxiety/Depression domain) were: MDE alone 2.6% (48.6%); anxiety alone 11.3% (38.7%); MDE and anxiety 5.2% (80.8%); and neither 80.9% (8.2%), respectively. Compared with subjects with neither condition, after adjustment for socio-demographic variables, mean EQ-Index and EQ-VAS scores were significantly lower for subjects with MDE and anxiety (0.70, 64.2), followed by those with MDE alone (0.83, 70.8) and anxiety alone (0.84, 76.7). CONCLUSIONS: Respondents with MDE or anxiety alone reported similar burden on the EQ-5D, overall and on the Anxiety/Depression domain. Comorbid MDE and anxiety is reflected in substantially lower EQ-5D scores. The EQ-5D performs reasonably well as a measure of general mental health, but more in-depth and specific measures would be required to identify and differentiate the impact of isolated mental health conditions on HRQL.