Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative strategy against a variety of malignant and nonmalignant disorders. However, acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) commonly complicate this approach, culminating in substantial morbidities and mortalities. The integumentary system is the preponderant organ involved in cGVHD, and its response to existing treatments, including well-versed immunosuppressants and novel targeted therapies, is not desirable. Despite the rarity, ulcers of sclerotic skin cGVHD are treatment-refractory and associated with significant morbidities and an exaggerated risk of infectious complications. Platelet-rich plasma (PRP) and its derivatives are endowed with growth factors and proangiogenic molecules and hold regenerative potential. This study aimed to assess the safety and efficacy of the application of platelet gel-containing dressing against ulcerative skin cGVHD in pediatric patients. This randomized trial is conducted at the hematopoietic stem cell transplantation unit of the Children's Medical Center Hospital in Tehran, Iran. Twenty-one pediatric patients (aged between 5 and 15 years) were initially enrolled, and 16 met the inclusion criteria. All cases (4 females) were recipients of allo-HSCT who had been complicated with symmetrically or near-symmetrically ulcerative sclerotic skin cGVHD. Fresh umbilical cord blood (UCB) was obtained from healthy donors and underwent centrifugation using a novel PRP preparation kit in a single-step process. Platelet gel was produced by adding thrombin to the isolated buffy coat layer. Two similar ulcers of each patient were randomized to receive either conventional dressing or platelet gels up to 6 times. At each time point evaluation, ulcer size and its relative reduction compared to the basal size were recorded. Included patients received a total of 80 platelet gel-containing dressings. While the mean sizes of randomized ulcers at the beginning of the study were similar, their differences became significant 15 days after the initiation of intervention (P = .019). In addition, the mean reduction in the ulcers’ surface area (in comparison to their baseline values) was significantly higher for the intervention arm at all evaluation points (P = .001 for day 5 and P < .001 for subsequent time points). At the end of the trial, the number of ulcers with a more than 50% reduction in size was 14 (87.5%) in the intervention arm (including 6 completely healed ulcers) versus 1 (6.25%, which was not completely healed) in the control arm (P < .001). None of the patients exhibited any localized or systemic treatment-related adverse events. In this study, using a relatively large number of cases, we showed that UCB-derived platelet gel is a safe, feasible, and effective curative approach for skin ulcers of sclerotic skin cGVHD in pediatric patients. Designing upcoming trials on the efficacy of this therapeutic approach for ocular, mucosal, and acute skin GVHD is prudent. Retrospectively registered at the Iranian Registry of Clinical Trials (registration number IRCT20190101042197N1) on August 24, 2020.