Background As the indications for postmastectomy radiotherapy expand, innovative solutions are required to reduce operative complications and reconstructive failure after prosthetic breast reconstruction. In this study, we investigated the effectiveness of acellular dermal matrix (ADM) inlay grafts in preventing postoperative wound dehiscence of irradiated breasts in the context of prosthetic breast reconstruction. Methods A retrospective analysis was conducted of 45 patients who received two-stage prosthetic reconstruction and radiotherapy following mastectomy. An ADM graft was placed beneath the incisional site during the second-stage operation in 19 patients using marionette sutures, whereas the control group did not receive the ADM reinforcement. Patient demographics and complications such as wound dehiscence, capsular contracture, peri-prosthetic infection, cellulitis, and seroma were compared between the two groups. Results During an average follow-up period of 37.1 months, wound dehiscence occurred significantly less often in the ADM-reinforced closure group (0%) than in the non-ADM group (23.1%) (P=0.032). There was no significant difference between the two groups in relation to other complications, such as capsular contracture, postoperative infection, or seroma. Conclusions The ADM inlay graft is a simple and easily reproducible technique for preventing incisional dehiscence in the setting of radiotherapy after prosthetic breast reconstruction. The ADM graft serves as a buttress to offload tension during healing and provides a mechanical barrier against pathogens. Application of this technique may serve to reduce complications in prosthetic breast reconstruction after radiotherapy.