LyphoDerm (XCELLentis, Belgium) is an end-sterilized, freeze-dried lysate from cultured allogeneic epidermal keratinocytes, formulated into a hydrophilic gel. Its efficacy and safety were evaluated, in combination with standard care (hydrocolloid dressing and compression therapy), in 194 patients suffering from hard-to-heal (lasting more than 6 weeks and not responding to conventional therapy) venous leg ulcers. Two control groups received standard care, with or without vehicle, respectively. Patients had a median age of 67.5 years and the majority were females (61%). The median duration of the ulcer was 43 weeks and in 39% of the subjects it had been present for more than 1 year. Thirty-eight percent of the patients in the standard care + LyphoDerm group had complete ulcer healing within 24 weeks (primary end point) compared to 27% of patients in the standard care + vehicle pooled groups (P = 0.114) in the "as treated" intent-to-treat cohort (37% vs. 27% in the "as randomized intent-to-treat cohort; p = 0.137). In the subgroup of patients with enlarging ulcers, the difference between the two groups was significant (30% vs. 11%; p = 0.024 in the "as treated" intent-to-treat cohort and 31% vs. 9%; p = 0.005 in the "as randomized" intent-to-treat cohort). LyphoDerm was well tolerated and safe, and no differences in the frequency of adverse events were noted between the treatment groups. Although the primary objective of the study was not achieved, the exploratory analysis carried out in patients with enlarging ulcers suggests that LyphoDerm could offer a new prospect for the treatment of patients with venous ulcers that may prove to be a significant adjunct to the overall provision of care.