Objective: To determine the association between various levels of comorbid anxiety and depression with health-related quality of life and work-performance. Methods: Patients from an anxiety disorders program clinic completed the SF-36, Work Limitations Questionnaire, Work Productivity and Activity Impairment Questionnaire, Endicott Work Productivity Scale, and Work Performance Scale. The Beck Anxiety Inventory (BAI) and the Beck Depression Inventory (BDI) were used to determine the severity of anxiety and depression, respectively. Patients were categorized as lowBAI/lowBDI, highBAI/lowBDI, highBAI/lowBDI, and highBAI/highBDI. The influence of severity of anxiety/depression on the eight SF-36 scales, the SF-36 PCS and MCS, and each work-performance instrument scale score was determined using ANOVA with Scheffe post-hoc analyses. Multivariate linear regression assessed the combined association of BAI and BDI on SF-36 and work-performance scales, controlling for patient demographics. P values of <0.05 were statistically significant. Results: Ninety-one patients provided complete SF-36, BAI and BDI. Of these, 61 were employed. There were no differences in demographics between groups. Post-hoc analysis indicated that lowBAI/lowBDI patients had significantly higher MCS (41.2+10.9) compared to highBAI/lowBDI (MCS=29.9+8.3), lowBAI/highBDI (MCS=23.7+15.8), and highBAI/highBDI (MCS=17.4+9.9). The difference between highBAI/lowBDI and lowBAI/highBDI were not significant. HighBAI/highBDI was significantly different than the other groups (p<0.01). This pattern was similar for social function, role emotion, mental health. Physical-related SF-36 domains were generally not different between groups. The difference in work-performance scale scores followed the same general pattern of less impairment with lowBAI/lowBDI (for example, WPAI-Percent Impairment While Working scale 0.22+0.3) and highBAI/highBDI (WPAI Percent Impairment While Working 0.77+0.2), p<0.01. Other work scales followed a similar pattern. BDI routinely was more significant in regression models compared to BAI. Conclusion: Comorbid anxiety and depression greatly impair patients. Clinicians and researchers should measure the presence and severity of both mental illnesses when assessing their influence on health-related quality of life and work-performance.