BACKGROUND: Incisional negative-pressure wound therapy (iNPWT) is widely adopted by different disciplines for multiple indications. Questions about the most appropriate uses and value of iNPWT have been raised. METHODS: An open-label within-patient RCT was conducted in transgender men undergoing gender-affirming mastectomies. The objective was to determine the effect of iNPWT as a substitute for standard dressing and suction drains on wound healing complications. One chest side was randomized to receive the iNPWT intervention, and the other to standard dressing with suction drain. The primary endpoints were wound healing complications (haematoma, seroma, infection, and dehiscence) after three months. Additional outcomes were pain according to a numerical rating scale and patient satisfaction one week after surgery. RESULTS: Eighty-five patients were included, of whom 81 received both the iNPWT and standard treatment. Drain removal criteria were met within 24 h in 95 per cent of the patients. No significant decrease in wound healing complications was registered on the iNPWT side, but the seroma rate was significantly increased. In contrast, patients experienced both significantly less pain and increased comfort on the iNPWT side. No medical device-related adverse events were registered. CONCLUSION: Substituting short-term suction drains with iNPWT in gender-affirming mastectomies increased the seroma rates and did not decrease the amount of wound healing complications. Registration number: NTR7412 (Netherlands Trial Register).