OBJECTIVES: To examine the differential impact of a physical versus a mental co-morbid condition on the health state utility (HSU) of patients with an existing physical condition. METHODS: Four base physical (B-Phys) conditions were examined: arthritis, asthma, diabetes and migraine.  For each B-Phys, 5 physical co-morbidities (Co-Phys) were selected based on published clinical and epidemiologic studies; depression and anxiety were selected as the 2 mental co-morbidities (Co-Mental).  Mean HSUs (and 95% confidence intervals) were calculated for patients with only B-Phys and for patients with the B-Phys and either a Co-Phys or a Co-Mental. Data came from individuals (N=26,885) with one or two of the selected conditions who participated in the National Health and Wellness Study between 2007 and 2010. HSUs, calculated based on the SF-6D, were age- and gender-adjusted to reflect the mean age and gender composition of the sample.  RESULTS: Patients with a Co-Phys had lower HSUs (mean differences ranged from -0.018 for asthma, to -0.061 for diabetes) when compared to patients with only B-Phys.  However, these differences were substantially greater for subjects with a Co-Mental instead of a Co-Phys (mean differences ranged from -0.081 for asthma, to -0.093 for arthritis).  The mean difference between the HSUs of patients with only the B-Phys and those of patients with both B-Phys and Co-Mental were between 1.4 (Diabetes) and 4.5 (Asthma) times higher than the difference between patients with B-Phys and B-Phys and Co-Phys. CONCLUSIONS: Economic evaluations of interventions are often based on published utilities among patients with a specific condition regardless of their other co-morbidities. Our results suggest that having a Co-Mental has a substantially greater impact on HSUs than a Co-Phys.  Studies aimed at evaluating interventions among patients with a particular condition must take into account the prevalence and type of co-morbidities among the population of interest.