18 patients with malignant effusions were treated with continuous intraperitoneal, intrapleural, or intrapericardial infusion of methotrexate (MTX) 30 mg/m2 per d combined with simultaneous intravenous administration of leucovorin at a dose rate calculated to yield an equimolar concentration in the serum. In the serum the geometric mean steady-state MTX concentration was 0.95 microM, whereas it was 24 microM in the peritoneal, 213 microM in the pleural, and 434 microM in the pericardial cavities. Mean clearance was 6.6 ml/min from the peritoneal cavity, 2.6 ml/min from the pleural cavity, and 0.14 ml/min from the pericardial cavity. Leucovorin provided sufficient protection to allow the duration of infusion to be escalated from 24 to 120 h before myelosuppression was encountered. Marrow thymidylate synthetase activity was inhibited by an average of 46% compared to 86% inhibition in malignant cells in the effusions. Flow cytometric analysis showed no perturbation of the cell cycle phase distribution of marrow cells. All eight of the evaluable patients have responded: three received no other form of therapy, five also received systemic hormonal or chemotherapy. This study demonstrated that tumors confined to third space body fluids can be given very high concentration x time exposures to MTX with minimal systemic toxicity.