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Purpose: To evaluate exogenous hyaluronic acid (HA) derived from bacterial fermentation through enteral and parenteral routes in ischemic skin flaps induced in rats, using clinical and histological exams; and interleukins (IL) as tissue inflammatory biomarkers., Methods: Sixty-four male adults Wistar rats with ischemic skin flaps on the dorsum were randomized into four groups, based on the treatment protocol: subcutaneous administration of saline solution (0.9%) (GI); oral administration of distilled water (GII); subcutaneous administration of HA (0.3%) (GIII); and oral administration of HA (1%) (GIV). Flaps of all groups were comparable regarding clinical and macroscopic evaluation, histological examination, pro-inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) and anti-inflammatory cytokine IL-10., Results: A lower percentage of necrosis was identified in flaps treated with subcutaneous administration of HA (0.3%). The pro- and anti-inflammatory cytokines, epidermis thickness, blood vessels, and inflammatory cells showed statistically significant inter-group and intra-group differences (p < 0.05)., Conclusions: High molecular HA (1,400 ~ 2,000 kDa) administrated by subcutaneous or oral route exhibited beneficial effects in ischemic skin flaps of rats. However, subcutaneous administration of HA (0.3%) showed better results in terms of the percentage of necrosis and epithelialization.