To assess the proportion of comorbidities in patients with dry eye disease (DED) compared with matched patients without DED in a comprehensive US population. DESIGN: Retrospective case-control study. METHODS: Healthcare records for insurance claims data, detailing medical services incurred by military personnel and their families and dependents in military and civilian facilities across the United States from January 1, 2003, to March 31, 2015, were obtained from the Department of Defense (DOD) Military Health System (MHS). Diagnostic and procedural codes related to DED from selected International Classification of Diseases, Ninth Revision (ICD-9) Current Procedural Terminology codes and prescriptions for cyclosporine A ophthalmic emulsion were used to identify patients with newly diagnosed and prevalent DED in the MHS database. Age, sex, and geographically matched patients without DED were also identified from healthcare claims records. Medication use and comorbidities in these patient populations were assessed and compared. RESULTS: In both the newly diagnosed and prevalent DED samples, the most common comorbidities were hypertension, cataracts, thyroid disease, type 2 diabetes, and glaucoma. All comorbidities were significantly higher in the DED vs non-DED groups (P < .001). Medication use (including, but not limited to, ophthalmic agents and drugs to treat comorbidities) was also significantly higher in the DED than in the non-DED groups (P < .001). CONCLUSIONS: The high proportions of patients with DED with a range of comorbidities and prescribed medications highlight the need for a multidisciplinary approach to the management of these patients.