Purpose: To evaluate the clinical characteristics, outcomes, and adverse reactions after the use of lifitegrast 5% ophthalmic solution for the treatment of patients with dry eye disease (DED). Methods: Retrospective chart review was performed in 121 patients seen at the Duke Eye Center with DED who were prescribed lifitegrast 5% and seen for follow-up after treatment initiation. Charts were reviewed for meibomian gland dysfunction (MGD) grading, conjunctival and corneal staining scores, and tear breakup time (TBUT), as well as matrix metalloproteinase-9 (MMP-9) levels. Ocular Surface Disease Index (OSDI) questionnaire scores and self-reported adverse reactions were also assessed. Results: The average patient age was 60.5 years (range, 22–88 years); 87.6% were female, and 20.7% had a previous autoimmune disease diagnosis. Of the 54 eyes with an initial positive MMP-9, 21 eyes (38.9%) normalized after treatment. The ocular symptoms OSDI subscore demonstrated an improvement of −2.43±6.85 ( P =0.011) after treatment. Corneal staining scores showed an average change of −0.15 ( P =0.007). The average change in TBUT was 1.9 sec ( P <0.001). Self-reported adverse reactions were noted in 31.4% of patients. There was no statistically significant change in MGD grading. Patients with moderate-severe DED showed statistically significant improvements in conjunctival and corneal staining scores and TBUT (−0.17±0.66, P =0.0442; −0.54±0.65, P <0.001; +2.02±2.63, P =0.004, respectively). Conclusion: Lifitegrast 5% is a useful therapeutic option for DED with a moderate proportion of self-reported adverse reactions, all of which were related to ocular discomfort. Treatment with lifitegrast was associated with statistically significant improvements in MMP-9 levels, ocular symptoms, corneal staining, and TBUT.