Background Maintaining robust perfusion is an important physiologic parameter in wound healing. The effect of different closure techniques on wound perfusion after total knee arthroplasty (TKA) has not been established previously and may have implications for wound healing. Questions/purposes We asked whether a running subcuticular, vertical mattress, or skin staple closure technique enables the most robust wound perfusion after TKA as measured by laser-assisted indocyanine green angiography (LA-ICGA) in patients without specific risk factors for wound healing complications. Methods Forty-five patients undergoing primary TKA without comorbidities known to impact wound healing and perfusion were prospectively randomized to receive superficial skin closure with one of the following techniques: (1) running subcuticular (3-0 monofilament); (2) vertical mattress (2-0 nylon); or (3) skin staples. Twenty procedures were performed by RTT, 15 by RJS, and 10 by FHS. All surgeons used an anterior skin incision over the medial third of the patella in combination with a median parapatellar arthrotomy. Perfusion was assessed with a LA-ICGA device and software system immediately after closure to quantify fluorescence. Twenty-seven points were assessed immediately after closure in the operating room in each patient (nine along the incision and nine pairs medial and lateral to the incision). Mean incision perfusion was determined from the nine points along the incision with One of the authors (RJS) lists the following relevant financial activities outside of this work and/or any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, this manuscript: Lifecell Corporation (Branchburg, NJ, USA) in an amount of less than USD 10,000 and Biomet Inc (Warsaw, IN, USA) in an amount of USD 10,000 to USD 100,000. One of the authors (MJT) lists the following relevant financial activities outside of this work and/or any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, this manuscript: DJO Global (Vista, CA, USA) in an amount of less than USD 10,000. One of the authors (RTT) lists the following relevant financial activities outside of this work and/or any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, this manuscript: DePuy Orthopaedics, Inc (Warsaw, IN, USA) in an amount of USD 10,000 to USD 100,000. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. higher values indicating greater blood flow. Mean perfusion impairment was determined by calculating the difference between the nine pairs of surrounding skin and the nine points along the incision with smaller values ind...