Abstract Introduction Primary thyroid lymphoma is extremely rare and accounts for <5% of all thyroid malignancies, with an estimated incidence of 2 per 1 million each year. It usually occurs in patients with preexisting Hashimoto thyroiditis and commonly presents between 60 to 70 years. Almost all thyroid lymphomas are non-Hodgkin's lymphoma of B-cell origin, with diffuse large B-cell lymphoma being the most common subtype. Chemotherapy and radiotherapy are the primary treatment of thyroid lymphomas. This case report shows a dramatic response to chemotherapy in a patient with mechanical airway obstruction due to large thyroid lymphoma, which facilitated her extubation. Case Presentation An 83-year-old woman with a past medical history significant for type 2 diabetes, coronary heart disease, and hypothyroidism controlled on L-thyroxine replacement therapy was presented with 3 months history of gradually progressive dysphagia. It was associated with left-sided neck pain with swallowing, choking on food, and shortness of breath. She denied fever, chills, or excessive sweats. Local examination of her neck revealed a large firm thyroid mass associated with left cervical lymphadenopathy. Her CT neck scan with intravenous contrast showed an enlarged, probably malignant thyroid gland with marked amount of adjacent pathologic lymph nodes and marked transverse narrowing of the trachea to approximately 8.6 mm with no retrosternal extension. Also, Her CT abdominal scan with intravenous contrast showed a 3.6 cm lesion of the medial right hepatic lobe (segment 8) concerning for metastases. The patient underwent an ultrasound-guided thyroid biopsy, and the results confirmed the diagnosis of diffuse large B cell lymphoma of the neck and thyroid. A few days later, the patient experienced respiratory distress and failure secondary to mechanical airway obstruction that required urgent intubation and mechanical ventilation. The discussion among different specialties, including general surgery, concluded that the patient was not a candidate for surgical intervention or tracheostomy, and recommendations were to proceed to palliative chemotherapy. She started R-CHOP chemotherapy (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), followed by a marked reduction in the thyroid size and relieving of the tracheal compression on the following CT neck scan. Her condition dramatically improved, and she was extubated after 5 days of receiving the first cycle of R-CHOP chemotherapy. Conclusion Our case report demonstrates dramatic reversal of mechanical airway obstruction caused by a thyroid lymphoma within a few days of initiation of R-CHOP chemotherapy. These cases are usually considered terminal and do not undergo aggressive surgical interventions. R-CHOP chemotherapy needs to be considered in these cases before considering hospice care. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m.