OBJECTIVES: Diabetes mellitus has been defined as one of the global epidemics of chronic diseases by the World Health Organization. Patients with diabetes are at an increased risk of developing macrovascular disease. The purpose of this study was to examine the marginal impact of macrovascular comorbidities on health-related quality of life (HRQoL) of patients with diabetes in a United States nationally representative sample. METHODS: Using the pooled Medical Expenditure Panel Survey (MEPS) 2001 and 2003 data, a nationally representative adult sample (age ≥18) was included in the study. The HRQoL outcomes included the SF-12 physical component summary (PCS) score, SF-12 mental component summary (MCS) score, EQ-5D preference-based index score, and visual analog scale (VAS). Ordinary least square regressions were used to identify the relationship between macrovascular disease conditions and PCS (and MCS) after controlling for age, sex, race, ethnicity, education, income, smoking status, health insurance, proxy response, and number of other comorbid categories. Due to the distributions of the EQ-5D preference-based index and VAS score, censored linear deviations estimator (CLAD) regressions were employed. All statistics were adjusted using the proper sampling weight from the MEPS. RESULTS: The average PCS, MCS, EQ-5D index, and VAS scores for patients with diabetes were 40.5, 48.5, 0.75, and 66.6, respectively for the sample. Compared to diabetes patients without macrovascular comorbidities (N=2,809), those with macrovascular comorbidities (N=654) had statistically significant lower PCS (-3.38, p<0.001), MCS (-1.43, p<0.05), EQ-5D index (-0.024, p<0.05), and VAS scores (-4.93, p<0.001). Patients with diabetes also had significantly lower HRQoL outcomes than those without diabetes (N=43,326) (p<0.001). CONCLUSIONS: In summary, macrovascular comorbidities significantly decrease HRQoL in patients with diabetes.