A 52-year-old previously healthy Caucasian woman presented with superior vena cava syndrome, secondary to compression of a bulky anterior mediastinal mass involving the right lung. Fine-needle aspiration biopsy of the mediastinum yielded large epithelioid cells intermingled with small mature lymphocytes. The epithelioid cells are LCA positive, expressing cytoplasmic CD3 diffusely and TIA-1 focally, but negative for EMA, CD4, CD8, CD15, CD20, CD30, and CD56. The TIA-1+ cytoplasmic granules correlated to the azurophilic granules in Diff-Quik-stained cells, pink granules in Ultrafast Papanicolaou-stained cells, and dense core granules in electron microscopy. In situ hybridization for Epstein-Barr viral RNA was negative. The background small lymphocytes were composed of a majority of CD4+ T-lymphocytes and minority of CD8+ T-lymphocytes. The patient responded well to six cycles of CHOP chemotherapy, followed by radiation with a total dose of 4140 cGy delivered to the mediastinum in 23 fractions. On the chest X-ray taken 6 mo later, there was minimal apical fibrosis with no evidence of an acute intrathoracic pathology. To the best of our knowledge, this case may be the first report of cytotoxic large T-cell lymphoma of the mediastinum.