Background: In breast reconstruction operations, surgical wound dehiscence is a serious complication that generates a significant burden on patients and health care systems. There are indications that postoperative treatment with closed-incision negative-pressure therapy has been associated with reduced wound dehiscence rates. This randomized clinical trial examines the effect of closed-incision negative-pressure application on abdominal donor-site surgical wound dehiscence in low- and high-risk patients undergoing breast reconstruction with a deep inferior epigastric perforator flap. Methods: Eighty eligible women, stratified as low- or high-risk patients, were included and were randomized for treatment with either closed-incision negative-pressure or adhesive strips by drawing sealed, opaque envelopes. All surgeons were kept blinded for allocation. Primary outcomes were surgical wound dehiscence and surgical-site infection at the abdominal donor site on follow-up after 12 weeks. Secondary outcomes were seroma and hematoma formation. Five patients were excluded from the study because of insufficient exposure to the study treatment (n = 4) or major protocol deviation (n = 1). Results: A total of 75 women, low-risk (n = 38) and high-risk (n = 37), received either closed-incision negative-pressure (n = 36) or adhesive strips (n = 39). Patients’ demographics did not differ significantly. Donor-site surgical wound dehiscence occurred in 23 patients; the absolute risk reduction was statistically significant (21.6 percent; 95 percent CI, 1.5 to 41.7 percent). No statistically significant differences were found in surgical-site infection or secondary outcomes. Conclusion: In this randomized clinical trial, postoperative treatment with closed-incision negative-pressure therapy decreased the incidence of surgical wound dehiscence at the abdominal donor site in low- and high-risk deep inferior epigastric perforator flap breast reconstruction patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.