Introduction. Evidence of the role of hyaluronic acid (HA) in the tissue repair process is extensive. Hyaluronic acid produces a positive effect on skin ulcer healing, so many companies produce it in various topical applications. Objective. This retrospective, observational study examined the use of different HA-based products in patients with chronic skin ulcers of various etiologies (vascular, scleroderma, postoperative) to assess the indication, effectiveness, and possible adverse reactions. Materials and Methods. A retrospective case review was conducted on 79 patients presenting to the Department of Dermatology of the Spedali Civili (Brescia, Italy) with multiple chronic skin ulcers of the legs of various etiologies. The authors counted a total of 106 chronic wounds with granulating appearance but not responsive to common wound dressings; for this reason, these wounds were treated with a HA-based product. The efficacy of the treatment was evaluated by dividing the population into 2 groups: sclerodermic (41 ulcers) and nonsclerodermic (65 ulcers). Results. Initial results confirmed HA-based products were effective for healing chronic skin wounds. However, when wounds are grouped by etiology, it was evident that patients with sclerodermic ulcers showed a rapid inflammatory response that led to a clinical deterioration and worsening of skin ulcers (92.7%). In contrast, patients with noninflammatory ulcers (vascular, postoperative) had the severe inflammatory event reduced to 1.5%, with a recovery of 98.5%. Conclusions. The negative effects of HA-based products on a patient with scleroderma could be explained by the fact that HA can produce a proinflammatory effect causing keratinocyte migration.