Cold atmospheric plasma (CAP) was shown to decrease bacterial load in chronic wounds. It was also presented as a novel approach to healing wounds in both in vitro and in vivo experiments. We aimed to examine the first randomized clinical trial for the use of CAP in diabetic foot ulcers. Patients (n = 44) were randomly double-blinded, and assigned to receive standard care (SC, n = 22) without or with CAP, to be applied three times a week for three consecutive weeks (SC + CAP, n = 22), using block randomization with mixing block sizes of four. The trial was conducted at the Diabetes Research Center in Tehran, Iran. CAP was generated from ionized helium gas in ambient air, and driven by a high voltage (10 kV) and high frequency (6 kHz) power supply. Primary outcomes were wound size, number of cases reaching wound size of <0.5, and a bacterial load after over three weeks of treatment. CAP treatment effectively reduced the fraction of wound size (p = 0.02). After three weeks, the wounds to reach fraction wound size of ≤0.5 was significantly greater in the SC + CAP group (77.3%) compared to the SC group (36.4%) (p = 0.006). The mean fraction of bacterial load counted in each session 'after CAP exposure' was significantly less than 'before exposure' measures. CAP can be an efficient method to accelerate wound healing in diabetic foot ulcers, with immediate antiseptic effects that do not seem to last long. Diabetes mellitus (diabetes) accounts for 3.9% of annual non-communicable disease-related deaths that occurred worldwide and also caused significant morbidity, impairing the patients' quality-of-life 1. Diabetic foot syndrome (DFS) is directly associated with diabetes, contributing to significant morbidity, as well as economic and social burden 2. It is estimated that approximately 25% of diabetic patients will develop DFS in their lives 3. Some authors reported that patients have a 3 to 11% annual risk of developing lower-extremity ulcers 2. Despite optimal treatment, diabetic ulcers are refractory to wound healing, with more than 50% recurring in the wounds after three years 4. Diabetic foot infection can also lead to complications, e.g., delayed healing process, systemic infections, and amputation. In addition, over 15% of patients with DFS experiences a lower limb amputation 5. The survival rate is found to be significantly lower in patients who require a lower limb amputation. The cost for two years of care with a newly-diagnosed foot ulcer is over $2,700 5. This has prompted more research and studies to identify viable alternatives or additive treatment options. Cold atmospheric plasma (CAP) is an innovative approach in wound healing. In vitro 6 and initial clinical studies for chronic wounds in animals 7,8 and humans 9-12 have shown that CAP decreases their bacterial load and promotes healing without any significant side effects on normal tissue. Additionally, CAP was found to facilitate the transformation of the chronic wound from becoming a stagnating wound or an acute healing wound through modulation of the i...