Topical zinc is widely used in wound treatment although the beneficial effect of zinc has only been documented in zinc-deficient patients who were given zinc orally. The main purpose of this study was to investigate the effect of topically applied zinc on leg ulcer healing and examine its effect on some mechanisms in wound healing using standardized animal models. Additionally, absorption of zinc into wounds and intact skin treated topically with zinc was studied. In a double-blind trial involving 37 leg ulcer patients with low serum zinc levels, topical zinc oxide promoted cleansing and re-epithelialization. Infections and deteriorations of ulcers were less common in zinc oxide treated patients. Re-epithelialization, an important mechanism in the closure of leg ulcers, was enhanced with zinc oxide applied topically on partial-thickness wounds in pigs with normal zinc status. Zinc sulfate at three different concentrations did not, however, result in this beneficial effect on the resurfacing of wounds. The inflammatory reaction was diminished in zinc treated wounds except when a high zinc sulfate concentration was applied. Bacterial growth and concomitant diseases such as diabetes can complicate wound healing. In normal rats, bacterial growth in full-thickness wounds was reduced with topical zinc oxide but not in hyperglycemic diabetic rats. The anti-bacterial mechanism of zinc oxide seemed to be more indirect and to be mediated via local defense systems rather than being directly toxic to the bacteria. Healing of 21-day-old skin incisions was impaired in zinc deficiency, as measured by a significantly decreased wound breaking strength in zinc-deficient rats compared with that of pair-fed controls. The decreased breaking strength did not seem to be due to differences in collagen concentration of the wounds. Zinc oxide was slowly but continuously solubilized when applied on open wounds in rats. On the other hand, with zinc sulfate, the zinc concentrations, either locally or systemically, did not maintain a constant level for the 48-hour post-operative treatment period as they did with zinc oxide. Zinc absorption in and through normal human forearm skin was demonstrated after treatment with a zinc oxide medicated occlusive dressing by increased zinc levels in epidermis, interstitial fluid and dermis compared with the non-zinc control dressing. In conclusion, topical zinc may stimulate leg ulcer healing by enhancing re-epithelialization, decreasing inflammation and bacterial growth. When zinc is applied on wounds it not only corrects a local zinc deficit but also acts pharmacologically.(ABSTRACT TRUNCATED AT 400 WORDS)