Large symptomatic pericardial effusion (PE)-PE that causes hemodynamic compromise-can be the initial presentation of an unrecognized underlying malignancy. However, the prevalence and features of this association have not been thoroughly characterized.We performed a retrospective study of all patients with hemodynamically significant PE who underwent pericardiocentesis in a 9-year period (1995-2004) in a tertiary hospital. Etiologies of pericardial disease were diagnosed using predetermined criteria. Demographic and clinical data of patients with hemodynamically significant PE as the presentation of their malignant disease were compared to those with established neoplastic disease, and to those with other etiologies.We identified 173 patients who underwent pericardiocentesis during the study period. Neoplastic PE was found in 58 patients (33%), 45 of whom had a known malignant disease at the time of pericardiocentesis. Pericardial disease was found to be the presentation of an unrecognized underlying neoplastic disease, mostly a lung tumor, in 13 patients (7.5% of all etiologies). After exclusion of pericardial effusions with easily attributable causes by clinical circumstances, physical examination, and simple laboratory tests (traumatic, uremic, post-pericardiotomy, rheumatic, and effusions related to known neoplasia), newly found cancer accounted for 18% of the remaining 74 cases. No epidemiologic or clinical parameter was found useful to differentiate between cancerous and noncancerous effusions.In conclusion, a large symptomatic PE may be the presentation of an unrecognized underlying malignancy in approximately one-fifth of the patients with a nonrevealing basic workup. This grave diagnosis cannot be ruled out on the basis of any clinical parameter. Thus, a more extensive workup should probably be considered in this patient group.