Lower leg ulcers are a serious and long‐term complication in patients with diabetes and pose a major health concern because of the increasing number of patients diagnosed with diabetes each year. This study sought to evaluate the clinical benefit of topical activated protein C (APC) on chronic lower leg ulcers in patients with diabetes. Twelve patients were randomly assigned to receive either APC (N = 6) or physiological saline (placebo; N = 6) in a randomised, placebo‐controlled, double‐blind pilot clinical trial. Treatment was administered topically, twice weekly for 6 weeks with final follow‐up at 20 weeks. Wound area was significantly reduced to 34·8 ± 16·4% of week 0 levels at 20 weeks in APC‐treated wounds (p = 0·01). At 20 weeks, three APC‐treated wounds had completely healed, compared to one saline‐treated wound. Full‐thickness wound edge skin biopsies showed reduced inflammatory cell infiltration and increased vascular proliferation following APC treatment. Patient stress scores were also significantly reduced following APC treatment (p < 0·05), demonstrating improved patient quality of life as assessed by the Cardiff Wound Impact Questionnaire. This pilot trial suggests that APC is a safe topical agent for healing chronic lower leg ulcers in patients with diabetes and provides supporting evidence for a larger clinical trial.