Malignant pericardial effusion, although highly variable, is an uncommon complication of cancer. It is often associated with symptoms like dyspnea, chest pain, and cough, which may be severe and disabling. We analyzed the results of our current treatment policy to evaluate the effectiveness and tolerance of a new approach for this disorder. Patients with malignant pericardial effusions were treated with intracavitary thiotepa (15 mg on days 1, 3, and 5) through an indwelling pericardial cannula after extraction of as much pericardial fluid as possible on day 0. Responses were assessed by clinical examination, computed tomographic (CT) scan, and echocardiography before treatment, 1 month after treatment, and every 2 months thereafter. Twenty-three patients with malignant symptomatic pericardial effusion were treated and all were assessable for effectiveness and tolerance of the procedure. Nine patients with breast cancer, 11 with lung cancer, two with an unknown primary tumor, and one with metastatic melanoma were treated. In all but three patients, systemic medical treatment was started after completion of intracavitary therapy. Nineteen patients responded to treatment (83%; 95% confidence interval, 61% to 95%) with a rapid improvement of symptoms. The median time to pericardial effusion progression was 8.9 months (range, 1 to 26). No significant side effects were registered, except one patient who had transient grade III thrombocytopenia and leukopenia and one patient who had grade I leukopenia. A short course of intracavitary treatment with thiotepa is highly effective and well tolerated in the treatment of malignant pericardial effusion.