The purpose of this study was to investigate the relationship between alcohol dependence and health-related quality of life (HRQoL) in people with and without other selected psychiatric disorders. A sample of 127,308 Veterans Health Administration enrollees completed a survey that included questions about alcohol use and the Veterans SF-36, a well-validated measure of HRQoL. In addition, a Veterans Administration database was used to obtain respondents' past-year history of alcohol dependence and other psychiatric disorders. Comorbid psychiatric disorders significantly moderated or attenuated the relationship between alcohol dependence and HRQoL. Respondents with a history of alcohol dependence plus one or more other psychiatric disorders had significantly lower HRQoL in domains pertaining to psychological and social functioning than respondents with alcohol dependence only. Effect size differences (mean differences of clinical groups/pooled standard deviation) were large (greater than 0.80 of one standard deviation). Respondents with a history of alcohol dependence only vs. no history of alcohol dependence had poorer HRQoL. Effect size differences were small to moderate (between 0.20 and 0.50 of one standard deviation). Findings highlight the important moderating influence of comorbid psychiatric disorders in the relationship between alcohol dependence and HRQoL. As comorbid psychiatric disorders are often associated with poorer treatment outcome, findings also provide strong corroboration for the importance of treating other psychiatric disorders concurrently with alcohol dependence.