Background: Digital ulcers (DUs) in Systemic sclerosis (SSc) result from recurrent Raynaud’s phenomenon (RP) and microtrauma with high impact on quality of life. Medical use of ozone (triatomic oxygen) was initiated in the 19th century. Ozone has multiple therapeutic effects in wound healing due to the property of releasing nascent oxygen, which has been shown to stimulate antioxidant enzymes. We aimed to assess the effects of ozone therapy on the healing of scleroderma DUs and determine levels of expression of vascular endothelial growth factor (VEGF), and endothelin-1 type A receptor (ETAR) autoantibodies in the wounds after treatment. Subjects and Methods: Fifty SSc female patients with DUs, were randomized into ozone group (I) (n=25) treated by calcium channel blockers plus oxygen-ozone treatment and control group (II) (n=25) treated by calcium channel blockers only. Ozone group received noninvasive oxygen-ozone treatments for 30 minutes per day for 20 days using the ozone generator device. Therapeutic effects were graded into 4 levels according to Zhang and other researchers. The wounds sizes were measured at baseline and day 20, respectively. Expressions of VEGF and ETAR autoantibodies proteins were determined by immune-histochemical examination. Results: Demographics and clinical characteristics of the 2 groups showed no significant differences. At day 20, the effective healing rate was significantly higher in group (I) than in group (II), where it represented 96% (24/25) in ozone group versus 44% (11/25) in control group, and (𝑃 = 0.007). After treatment, the wound sizes in both groups were significantly smaller than before treatment. In group (I), the wound size reduction was significantly more than in group (II) (0.75 ± 0.30 versus 2.44 ± 0.80 mm), (𝑃 = 0.00). At day 20, VEGF was significantly higher in ozone group (I), than in control group (II), (83.96±9.68) versus (67.92±6.55), (𝑃 = 0.00) while, ETAR was significantly lower in ozone group (I), than in control group (II), (3.14±1.12 versus 4.59±1.24), (𝑃 = 0.00). Conclusion: Ozone therapy may be beneficial tool in the treatment of DUs in SSc patients, where it promotes the wound healing through a potential induction of VEGF and down-regulation of ETAR at sites of the ulcers.