Background: Negative Pressure Wound Therapy (NPWT) has proven to be an effective intervention in preventing postoperative complications across a range of surgical specialties, including orthopedics, vascular, and abdominal surgery. This study aimed to assess the prophylactic use of NPWT dressing compared to the Standard of Care (SOC) in high-risk patients undergoing oncoplastic and reconstructive breast surgery. Materials and Methods: This preliminary case-control study included 23 high-risk patients, enrolled between September 2023 and February 2024, at San Martino Polyclinic Hospital, Genoa. High-risk patients were defined as those with one or more of the following risk factors: obesity, prior radiotherapy, neoadjuvant chemotherapy, smoking history, diabetes, or corticosteroid use. The surgical procedures evaluated in this study included mastectomy with immediate implant-based breast reconstruction, reduction mammoplasty, and oncoplastic breast surgery following local excision or quadrantectomy. NPWT dressing was applied immediately after skin closure in the operating room, replaced after 2–3 days, and removed 7 days post-procedure. Surgical outcomes assessed included skin flap necrosis, wound dehiscence, infection, implant loss, and delays in adjuvant therapy. Results: A total of 23 patients, aged 45 to 57 years, were enrolled. Eleven patients received NPWT dressing, while twelve were treated with SOC. No complications occurred in the NPWT dressing group, whereas four complications were observed in the SOC group. Of the control group, three patients developed infections, which were treated with oral antibiotics for two, while one required implant replacement surgery. The remaining patient in the control group experienced wound dehiscence, which was successfully managed conservatively on an outpatient basis. Discussion and Conclusions: Our findings suggest that prophylactic NPWT dressing in oncoplastic and reconstructive breast surgery results in a significantly lower rate of wound-related complications. Although this is a preliminary study, it provides a foundation for further research in a larger cohort. These results also prompt a discussion of the cost-effectiveness of NPWT dressing relative to the SOC, given its higher cost.