Aim In patients with diabetes or ischemia, angiogenesis and infection control are required for chronic leg ulcers, which substantially impair patients’ quality of life. We developed a novel functional peptide, named AG30/5C, with angiogenic and anti‐microbial properties. Treatment with AG30/5C significantly accelerated the wound healing of full‐thickness defects in mice. To evaluate the safety of AG30/5C in the treatment of leg ulcers, a physician‐initiated clinical study was carried out. Methods The first‐in‐human trial was designed as an open‐label treatment with AG30/5C (0.1 mg/mL) given twice per day for 11 days, and with a follow‐up period of 17 days. The inclusion criteria for severe skin ulcers were: (i) diabetes or critical limb ischemia; (ii) resistance to standard therapy for 1 month; and (iii) detection of methicillin‐resistant Staphylococcus aureus in the skin ulcer. Results Four patients were enrolled in this study, and two patients met these criteria. For the evaluation of safety, three adverse effects were reported as possibly related to AG30/5C treatment; however, these adverse effects were not severe and resolved during or after treatment. Thus, there were no safety concerns. In both patients, the size of the ulcer decreased after treatment (44.62% and 10.23% decrease), and further decreased after the follow‐up period (73.85% and 10.23% decrease). The former patient was diagnosed as Werner syndrome and the skin ulcer was resistant to standard therapy; however, it was sensitive to AG30/5C treatment. Conclusions Topical treatment with AG30/5C for severe leg ulcers was safe, well tolerated and effective. Geriatr Gerontol Int 2017; ••: ••–••.