Purpose <p>Immediate postmastectomy breast reconstruction in patients with history of breast-conserving surgery and radiotherapy presents unique challenges owing to previous surgical and radiation effects. This study evaluated the outcomes of implant-based and deep inferior epigastric perforator (DIEP) flap breast reconstruction in these patients.</p> Patients and Methods <p>Patients who underwent total mastectomy followed by immediate implant-based or DIEP flap breast reconstruction between 2010 and 2023 with history of breast-conserving surgery and radiotherapy were reviewed. Major complications, including infection, skin flap complications requiring surgical revision, and reconstruction failure, were compared using univariate and multivariate logistic regression.</p> Results <p>Among the 4306 immediate reconstructions, 105 cases met the inclusion criteria (70 implant-based and 35 DIEP flap reconstructions). The mean follow-up duration was 17.5 months in the implant-based group and 26.9&#xa0;months in the DIEP group. Reconstruction failure occurred in 15.7% of the implant-based group and 0% of the DIEP group (<i>p</i> = 0.015). Major complications were significantly more frequent in the implant-based group than in the DIEP group (24.3% vs. 5.7%, <i>p</i> = 0.020). Multivariate analysis revealed that implant-based reconstruction carried 8.0-fold higher risk of major complications than DIEP reconstruction (<i>p</i> = 0.010). Skin-sparing mastectomy was associated with a significantly higher risk of complications than nipple-sparing mastectomy (odds ratio [OR] = 4.6, <i>p</i> = 0.010).</p> Conclusions <p>In patients with prior breast-conserving surgery and radiotherapy, choosing a DIEP flap as a breast reconstruction modality may reduce complication risk compared with implant-based methods. These findings provide valuable guidance for preoperative patient counseling and surgical planning.</p>