This randomized study was designed to establish the efficacy of platelet-rich plasma (PRP) gel and topical estradiol alone, or in combination, on healing of full-thickness wounds created on the trunk of rabbits. Fifteen New Zealand white female rabbits and 60 wounds were studied. Four 2.25-cm² full-thickness wounds were created using a template and treatments including a sterile saline solution that were assigned randomly to the wounds. Wounds were bandaged, dressed intermittently, and assessed by wound measurements and a collection of samples at 7, 14, and 21 days to evaluate healing. Variables of interest were hydroxyproline concentration and scored gross and microscopic morphologic characteristics reflective of wound healing. PRP gel + estradiol-treated wounds completely healed faster than wounds given other treatments. Granulation tissue growth to the skin level was faster (P < 0.05) in the PRP gel + estradiol group than the other groups. Only the PRP gel + estradiol group had a significantly lower collagen level than the sterile saline solutions on day 7 (P < 0.05). The PRP gel + estradiol group and estradiol group led to an increase in angiogenesis on day 14 (P < 0.05). Complete epithelization was observed only in the PRP gel + estradiol group compared with the other groups on day 7. PRP gel + estradiol-treatment enhanced healing in full-thickness wounds by reducing the contraction rate with a trend toward accelerating both epithelial migration and the angiogenic response.