Introduction. Reports of retroperitoneal infection related to a sacral pressure injury (PI) are rare, and none of the reports described the direct spread of infection through the sacrum to the retroperitoneum. The authors present, to their knowledge, the first report of a severely infected PI that showed full-thickness sacral destruction and direct retroperitoneal penetration. Case Report. A 63-year-old female was referred for management of a stage 4 sacral PI complicated by a retroperitoneal abscess. The patient’s comorbidities were diabetes mellitus and pemphigus foliaceus with steroid therapy-induced immunosuppression. Upon admission, the patient presented with a sacral PI producing copious purulent discharge that measured 5 cm × 3 cm. Magnetic resonance imaging revealed full-thickness sacral bone destruction and a massive retroperitoneal abscess, suggesting the sacral PI directly penetrated to the retroperitoneal space. Antibiotics were administered, and surgical debridement and sequestrectomy were performed. Negative pressure wound therapy (NPWT) with continuous saline irrigation was initiated. The patient’s mesorectum was exposed within the retroperitoneal space. Therefore, a nonadhesive wound dressing was applied before placing the irrigation tube to avoid perforating the rectum. Because the patient had fragile skin secondary to long-standing pemphigus foliaceus and steroid treatment, a liquid skin protectant and hydrocolloid wound dressing were applied. The infection was successfully controlled with NPWT with saline irrigation. The patient experienced no rectal injury or skin rupture, and surgical closure was performed after 75 days. Although partial wound dehiscence occurred because of the poor condition of the skin, the resultant open wound was managed conservatively. The patient showed no retroperitoneal abscess recurrence 6 months later. Conclusions. A rare case of an intractable sacral PI complicated by retroperitoneal abscess was successfully managed in an immunocompromised patient. Notably, NPWT with saline irrigation was useful in controlling the patient’s severe retroperitoneal infection.