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Background: An increasing number of women who undergo immediate two-stage tissue expander/implant breast reconstruction will require postmastectomy radiation therapy. An important variable is the timing of radiotherapy relative to surgery. The authors report their experience treating a large consecutive series of patients who underwent postmastectomy radiation therapy to the tissue expander before exchange for a permanent implant., Methods: Patients who had their tissue expander irradiated before implant exchange were identified. Complications, capsular contracture, revision surgery, and autologous salvage rates of irradiated patients were compared with a control group of nonirradiated patients., Results: Immediate two-stage tissue expander/implant reconstruction was initiated in 604 patients, with 113 irradiated breasts meeting inclusion criteria. Three hundred thirty-nine nonirradiated breasts constituted the control group. There was a 4.2 increased odds of major complications in the irradiated group, after adjusting for plastic surgeon, age, body mass index, smoking, chemotherapy, and cancerous breast (OR, 4.2; p=0.001). The grade III and IV capsular contracture rate was significantly higher in the irradiated group compared with the control group (21.7 percent versus 10 percent; p<0.008). The revision rate in the control group was higher compared with the irradiated group (30.2 percent versus 20.9 percent; p<0.001)., Conclusions: Postmastectomy irradiation to the tissue expander is associated with high complications; however, these patients have an acceptable capsular contracture rate that compares favorably with other implant-based radiotherapy algorithms. Revision rates were less than expected in irradiated breasts. This study suggests that immediate tissue expander/implant reconstruction is a reasonable surgical option in the setting of postmastectomy radiation therapy., Clinical Question/level of Evidence: Therapeutic, III.