Pleural effusions and mediastinal masses are associated with certain types of hematologic malignancies. We report a 20-year-old man with a pleural effusion, a mediastinal mass, and a normal hemogram. The cytology of the pleural effusion initially suggested a lymphoma. However, an immunophenotypic study of the effusion revealed the following: TdT+, CD34+, CD19+, CD7(-), CD33(-), CD10(-), sIgM(-), and positive cytoplasmic mu heavy-chain immunoglobulins. After a bone marrow examination, we diagnosed the patient with pre-B acute lymphoblastic leukemia (ALL). This is the first reported case of a malignant pleural effusion and a mediastinal mass that preceded pre-B ALL. After standard therapy for ALL, the patient has been disease-free for 7 years.