Since its introduction into clinical practice in 1967 by Charles Fox Jr., silver sulfadiazine has been the gold standard for topical burn therapy. The addition to it of hyaluronic acid, which forms a substantial part of the human tissue intercellular matrix, is aimed at overcoming one of its very few disadvantages, i.e. prolongation of the wound re-epithelialization process. Since both hyaluronic acid and silver sulfadiazine have been used in therapy for decades and their efficacy is well documented, a topical treatment combining these two agents was formulated. The aim of the study was to investigate the efficacy and tolerability of a cream containing a hyaluronic acid/silver sulfadiazine fixed combination, compared with silver sulfadiazine cream alone, for the treatment of superficial and deep second-degree burns in a prospective, double-blind, controlled clinical study. The findings of the study confirmed that the association of the two compounds in a new topical treatment significantly reduced the healing time and significantly accelerated the reduction of local edema occurring shortly after injury. Furthermore, this new hyaluronic acid and silver sulfadiazine formulation has proven to have favorable antibacterial, anti-edematous and local analgesic effects, together with a clear stimulatory activity on the re-epithelialization process. This product may, therefore, significantly enrich the assortment of topical medications available for the treatment of burns and skin defects of other origin.