Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin with distinct clinicopathologic and radiographic features. Reports detailing the cytology of ECD are rare. We describe a case of ECD with pericardial effusion. Cytologic examination revealed a hypercellular specimen composed of clusters and singly dispersed foamy macrophages with round nuclei and inconspicuous nucleoli, admixed with lymphocytes, eosinophils, and Touton-type multinucleated giant cells. Immunostains for CD68 were strongly positive in the foamy macrophages while S100 and CD1a were negative. The presence of foamy histiocytes, multinucleated giant cells, lymphocytes and eosinophils are also features of other systemic histiocytic disorders, including Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD) and sarcoidosis. To the best of out knowledge, this is the first report describing the cytological features of ECD in a pericardial effusion. Diagn. Cytopathol. 2014;42:530–534. © 2013 Wiley Periodicals, Inc.