Many types of tumor cells overexpress transforming growth factor β (TGF-β), which is believed to promote tumor progression. We hypothesized that overexpression of the extracellular region of the type II TGF-β receptor (soluble TβRII) would compete for or block TGF-β binding to TβRs on immune cells, preventing TGF-β-mediated immunosuppression and consequently resulting in the eradication of tumor cells. We tested this in the mouse thymoma cell line EL4, which has been reported to suppress cellular immunity by secreting a large amount of TGF-β. Transduction of EL4 with recombinant retrovirus encoding soluble TβRII resulted in the secretion of heterogeneously glycosylated, 25 to 35 kDa truncated TβRII. Inoculation of 1 × 10⁴ to 5 × 10⁴ soluble TβRII-modified EL4 cells (EL4/Ts, EL4 cells transduced with recombinant retrovirus encoding soluble TβRII and neomycin resistance gene) s.c. to mice showed reduced tumorigenicity, as indicated by lower overall tumor incidence (7%, 1 of 14; P < 0.001) compared with unmodified EL4 (100%, 9 of 9) or vector-modified EL4 cells (EL4/neo, EL4 cells transduced with recombinant retrovirus encoding neomycin resistance gene; 100%, 4 of 4). Administration of mitomycin C-treated EL4/Ts cells (1 × 10⁶) after EL4 inoculation (1 × 10⁴) reduced tumor incidence from 100% (5 of 5 in mice inoculated with mitomycin C-treated EL4/neo) to 40% (4 of 10, P < 0.05), indicating that supply of soluble TβRII could actually block TGF-β-mediated tumorigenesis. In vitro tumor cytotoxicity assays revealed 3–5-fold higher cytotoxic activity with lymphocytes from EL4/Ts-bearing mice compared with those from EL4- or EL4/neo-bearing mice, indicating that the observed tumor rejection was mediated by restoration of the tumor-specific cellular immunity. These data suggest that expression of soluble TβRII is an effective strategy for treating highly progressive tumors secreting TGF-β.