A 65-year-old woman with a clinical history of right eye proptosis and conjunctival hyperemia was found to have a 2.8-cm orbital mass involving the right lacrimal gland (panel A), clinically thought to be an epithelial tumor. A biopsy demonstrated dense infiltration of small- to medium-sized cells with lymphoid appearance (panel B [original magnification ×400; hematoxylin and eosin stain]), but these cells were negative for CD3 (panel C [original magnification ×600; immunohistochemical stain]) and CD20 (panel D [original magnification ×600; immunohistochemical stain]). A retrospective chart review showed that the patient had a history of an acute leukemia, mixed phenotype (B/myeloid), diagnosed 7 years ago on a bone marrow biopsy with flow cytometric analysis. The patient had been in remission for 6 years. A battery of immunostaining was performed and revealed that the infiltrate in the orbital mass had similar immunophenotype to the previously diagnosed acute leukemia, including strong terminal deoxynucleotidyl transferase positive (panel E [original magnification ×600; immunohistochemical stain]), CD34 −, moderate CD117 +, partial CD10 +, partial PAX5 +, and aberrant expression of CD7. Positron emission tomography–computed tomography showed no additional hypermetabolic sites, and bone marrow examination was negative.This is a rare presentation of a relapse of an acute leukemia as an isolated orbital mass. This case illustrates the importance of interpreting morphologic findings within the clinical context, which includes not only the patient’s current clinical scenario but also the pertinent previous history. The clinical information not only places the morphologic findings in context but also guides the appropriate use of ancillary studies.