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Purpose: Mesothelin is a cell surface protein overexpressed in mesotheliomas and pancreatic and ovarian cancers. The goal of this study was to determine if radiation therapy in combination with the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) would result in enhanced antitumor activity against mesothelin-expressing xenografts in nude mice. Experimental Design: Female athymic nude mice bearing s.c. mesothelin-expressing xenografts were treated with SS1P alone, tumor-focused radiation alone, or the combination of the two. Two different regimens of the combination therapy were tested. In the low-dose combination schedule, mice were treated with either 5 Gy radiation alone, 0.2 mg/kg SS1P alone, or the same doses of radiation and SS1P in combination. In the high-dose combination experiments, mice were treated with either 15 Gy radiation alone, 0.3 mg/kg SS1P alone, or the combination of radiation and SS1P. Results: In the low-dose radiation and SS1P combination studies, mice treated with the combination of radiation and SS1P had a statistically significant prolongation in time to tumor doubling or tripling compared with control, SS1P, or radiation alone. A similar increase in time to tumor doubling or tripling was seen in mice treated with high-dose radiation and SS1P combination. Conclusions: Combination of SS1P with tumor-directed radiation results in enhanced antitumor activity against mesothelin-expressing tumor xenografts. This effect was seen when either low or high doses of radiation were used.