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A consensus is lacking on a uniform reconstructive algorithm for patients with locally advanced breast cancer who require postmastectomy radiotherapy. Both delayed autologous and immediate prosthetic techniques have inherent advantages and complications. The study hypothesis is that implants are more cost effective than autologous reconstruction in the setting of postmastectomy radiotherapy because of immediate restoration of the breast mound.A cost-effectiveness analysis model using the payer perspective was created comparing delayed autologous and immediate prosthetic techniques against the do-nothing option of mastectomy without reconstruction. Costs were obtained from the 2010 Nationwide Inpatient Sample database. Effectiveness was determined using the BREAST-Q patient-reported outcome measure. A breast quality-adjusted life-year value was considered 1 year of perfect breast health-related quality of life. The incremental cost-effectiveness ratio was calculated for both treatments compared with the do-nothing option.BREAST-Q scores were obtained from patients who underwent immediate prosthetic reconstruction (n = 196), delayed autologous reconstruction (n = 76), and mastectomy alone (n = 71). The incremental cost-effectiveness ratios for immediate prosthetic and delayed autologous reconstruction compared with mastectomy alone were $57,906 and $102,509, respectively. Sensitivity analysis showed that the incremental cost-effectiveness ratio for both treatment options decreased with increasing life expectancy.For patients with advanced breast cancer who require postmastectomy radiotherapy, immediate prosthetic-based breast reconstruction is a cost-effective approach. Despite high complication rates, implant use can be rationalized based on low cost and health-related quality-of-life benefit derived from early breast mound restoration. If greater life expectancy is anticipated, autologous transfer is cost effective as well and may be a superior option.