An animal model has been established to investigate the effect of intra-thecal (i.t.) immunotoxins in the treatment of leptomeningeal metastases of acute lymphoblastic leukaemia (ALL). Direct inoculation of b C lymphoma cells into the cisterna ma na of guinea-pigs gives rise to a leptomeningeal pattern of growth, similar to that of human ALL, and to a systemic leukaemia which develops in approximately 14 days. In our model the systemic disease could be controlled with cyclophosphamide while the meningeal disease progressed and provided a target for i.t. immunotoxin. The immunotoxin used consisted of an anti-idiotypic antibody disulphide-bonded to the ribosome-inactivating protein saporin. It was highly cytotoxic to b C cells in vitro, being around 30,000 times more potent than a control immunotoxin at inhibiting protein synthesis. In vivo, the maximum tolerated dose of i.t. immunotoxin was 10 pg. From the rate at which radiolabelled immunotoxins appeared in the plasma following i.t. injection, we were able to estimate that its half-life in the cerebrospinal fluid (CSF) was between 1% and 2 hr. Intrathecal treatment of guinea-pigs with immunotoxin I day after inoculation of b C cells into the cisterna magna had a remarkable therapeutic effect. All guinea-pigs treated with 0.5 or 5 Fg of immunotoxin survived, and remained tumour-free for more than 100 days after treatment, while control animals given cyclophosphamide alone or an irrelevant immunotoxin had a mean survival time of 28 days. Provided concerns over toxicity can be overcome, these results indicate that i.t. immunotoxins offer an alternative, highly specific form of treatment in leptomeningeal neoplasia.