This case report describes the detection of two synchronous malignancies by cytologic examination of pleural effusion fluid in a 66-year-old man. The effusion cytology examination documented an adenocarcinoma in the background of chronic lymphocytic leukemia. The cytologic findings were confirmed by surgical biopsy and ancillary studies performed on the cytology specimen including immunocytochemistry, flow cytometry and electron microscopy. This case is unusual and to the best of our knowledge the first reported case in the English literature of two synchronous malignancies being diagnosed by effusion cytology. When two separate populations of atypical cells are present in the cytology smears, the possibility of multiple malignancies should be considered.