To identify and characterize the subunit structure of interleukin-13 receptor (IL-13R) in human medulloblastoma cell lines and target them with a chimeric fusion protein consisting of interleukin-13 and Pseudomonas exotoxin (termed as IL-13 cytotoxin).Five human medulloblastoma cell lines were examined for the expression of IL-13R subunits at the mRNA and protein levels by reverse transcriptase-polymerase chain reaction (RT-PCR) and indirect immunofluorescence studies, respectively. In addition, IL-13 cytotoxin-induced cytotoxicity was examined in these medulloblastoma cell lines by measuring protein synthesis inhibition.All five medulloblastoma cell lines expressed mRNA and proteins for IL-4Ra and IL-13Ra1 chains, whereas three of the cell lines also showed the presence of IL-13Ra2. mRNA or protein for IL-2gc chain was not detected in any of the cell lines. Consistent with the expression of IL-13Ra2 chain, IL-13 cytotoxin was highly and specifically cytotoxic to three of five medulloblastoma cell lines. The sensitivity of medulloblastoma cell lines to IL-13 cytotoxin could be completely eliminated by concurrent incubation with excess of IL-13, but not with IL-2 or IL-4.These studies establish IL-13R, in particular IL-13Ra2, as a medulloblastoma-associated target for IL-13 cytotoxin therapy. IL-13 cytotoxin may be useful for medulloblastoma therapy. Alternatively, IL-13Ra2 may serve as a tumor-specific antigen for active immunotherapy.