The purpose of this study was to determine the accuracy and efficiency of a custom-designed immobilization device for patients with extremity soft-tissue sarcoma. The custom device consisted of a thermoplastic shell, vacuum pillow, and adaptable baseplate. The study included patients treated from January 2005 to March 2007, with 92 patients immobilized with the custom device and 98 with an established standard. Setup times for these cohorts were analyzed retrospectively for conformal and intensity modulated radiotherapy techniques (IMRT). Thigh tumor setup times were analyzed independently. A subset of patients treated with IMRT was analyzed for setup error using the radiographically verified isocenter position measured daily with electronic portal imaging and cone-beam computed tomography. Mean setup time was reduced by 2.2 minutes when using the custom device for conformal treatment (p = 0.03) and by 5.8 min for IMRT of thigh tumors (p = 0.009). All other setup time comparisons were not significant. A significant systematic error reduction was seen in all directions using the custom device. Random error standard deviations favored the custom device. The custom device offers immobilization advantages. Patient setup time was reduced for conformal techniques and IMRT of thigh tumors. Positioning uncertainty was improved, permitting a reduction of the planning target volume margin by 2 to 4 mm.