Purpose <p>Surgical site infection (SSI) of perineal wounds after abdominoperineal resection (APR) or total pelvic exenteration (TPE) for pelvic malignancies is a common postoperative complication. Although several attempts have been made to prevent this complication, SSI of perineal wounds remain common. The efficacy of prophylactic negative-pressure wound therapy (NPWT) in abdominal surgery has been reported; however, few studies have focused on perineal wounds, where the incidence of SSI is particularly high. This study investigated the prophylactic effect of NPWT on closed perineal wounds after APR/TPE to prevent SSI.</p> Methods <p>This study enrolled 127 consecutive patients with malignant tumors who underwent elective APR/TPE between January 2013 and December 2022. We used the Prevena™ incision management system (IMS) on the perineal wound in 10 patients for prophylactic NPWT (pNPWT group), whereas 117 patients underwent conventional primary closure (cPC group). We compared the incidence of perineal wound SSI between the groups and explored the risk factors associated with SSI.</p> Results <p>Patients’ backgrounds were essentially the same between the groups. There were no SSI cases in the pNPWT group, whereas 29 patients (25%) in the cPC group had SSI (<i>P</i> = 0.067). Exploratory analyses revealed that a body mass index ≥ 25, disinfection method, and neoadjuvant chemotherapy were significantly correlated with SSI in perineal wounds.</p> Conclusion <p>Prophylactic NPWT for closed perineal wounds after APR/TPE in patients with malignancies can be effective in preventing SSI.</p>