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Aims: Propolis is a naturally occurring anti-inflammatory bee derived protectant resin. We have previously reported that topically applied propolis reduces inflammation and improves cutaneous ulcer healing in diabetic rodents. The aim of this study was to determine if propolis shows efficacy in a pilot study of human diabetic foot ulcer (DFU) healing and if it is well tolerated. Materials: Serial consenting subjects (n = 24) with DFU ≥4 week's duration had topical propolis applied at each clinic review for 6 weeks. Post-debridement wound fluid was analyzed for viable bacterial count and pro-inflammatory MMP-9 activity. Ulcer healing data were compared with a matched control cohort of n = 84 with comparable DFU treated recently at the same center. Results: Ulcer area was reduced by a mean 41% in the propolis group compared with 16% in the control group at week 1 (P < 0.001), and by 63 vs. 44% at week 3, respectively (P < 0.05). In addition, 10 vs. 2% (P < 0.001), then 19 vs. 12% (P < 0.05) of propolis treated vs. control ulcers had fully healed by weeks 3 and 7, respectively. Post-debridement wound fluid active MMP-9 was significantly reduced, by 18.1 vs. 2.8% week 3 from baseline in propolis treated ulcers vs. controls (P < 0.001), as were bacterial counts (P < 0.001). No adverse effects from propolis were reported. Conclusions: Topical propolis is a well-tolerated therapy for wound healing and this pilot in human DFU indicates for the first time that it may enhance wound closure in this setting when applied weekly. A multi-site randomized controlled of topical propolis now appears to be warranted in diabetic foot ulcers. [ABSTRACT FROM AUTHOR]