Objective: To demonstrate the direct stimulation of thyroid tissue in the absence of thyroid-stimulating immunoglobulin after exposure to epoprostenol. Methods: Seronegative thyrotoxicosis, diffuse goiter, and homogeneous uptake on thyroid scintigraphy were noted in a patient with pulmonary arterial hypertension (PAH) being treated with intravenously administered epoprostenol (prostaglandin I2 or PGI2). More cases with similar characteristics were identified on review of the thyroid function in patients with PAH who were treated with this medication. Fifty-four adult patients with PAH were studied. The study subjects were divided into 2 groups based on whether they were treated with PGI2 or not. Thyroid functions were reviewed, and the prevalence of thyroid disease was assessed. We then compared the prevalence of hyperthyroidism in our study subjects with the prevalence of hyperthyroidism in the general female population using data from published studies. Results: We noted a high prevalence (3 of 45 or 6.7%) of thyroid-stimulating immunoglobulin-negative thyrotoxicosis in adults with preexisting PAH being treated with epoprostenol (PGI2) in the absence of other mechanisms or drugs to explain the hyperthyroidism. The prevalence of hyperthyroidism in our study population was significantly greater (P<.01 by χ2 analysis) than that in the general female population in other published reports. Conclusion: The data suggest that epoprostenol is a medication associated with stimulation of thyroid tissue, goiter formation, and hyperthyroidism. Patients receiving this drug need to undergo close follow-up for the development of thyrotoxicosis and goiter. (Endocr Pract. 2009; 15:116-121).