Purpose To study the efficacy of oral montelukast, a cysteinyl leukotriene receptor antagonist, in combination with cetirizine, a histamine-1 receptor antagonist, in the treatment of thyroid eye disease. Methods Patients considering surgical correction of eyelid retraction for inflammatory symptoms of thyroid eye disease were offered a preoperative medical regimen of oral montelukast/cetirizine. Exclusion criteria included prior use of oral montelukast (i.e., for seasonal allergy or asthma), compressive optic neuropathy, severe ophthalmopathy requiring systemic corticosteroids, and orbital and/or muscle surgery. A 6-week course of oral cetirizine (10 mg every morning) and oral montelukast (10 mg every evening) was administered and patients subjectively rated their ocular surface dryness, tearing, itching, injection, eyelid swelling, eyelid retraction, double vision, proptosis, and visual clarity, at baseline, after 3 weeks and 6 weeks of medical therapy, and after 3 weeks off of the medications. Results Six of the 12 patients recruited for the study reported a subjective improvement in tearing, dryness, and itching. Less effect on diplopia and proptosis was noted after 6 weeks of medical therapy. Two of the patients who did not report response chose to proceed with eyelid retraction surgery and both had evidence of mast cell infiltration in their Muller muscle specimens. Conclusion The response observed in this open-label trial suggests that oral montelukast and cetirizine may be an effective medical regimen for patients with thyroid eye disease who experience mild to moderate orbital congestion and inflammation.