The biological mechanisms underlying the use of platelet-rich plasma (PRP), as well as the efficacy and possible adverse effects of PRP, have not yet been fully elucidated. Prior studies have evaluated PRP for cutaneous ulceration. However, the benefits from PRP still remain controversial and few have assessed the effects of ulceration etiologies. The purpose of our study is to determine the efficacy and safety of PRP and which kind of ulcer is more suitable for PRP by analyzing the effects of PRP on ulcers with different causes. A comprehensive search was performed to identify randomized controlled trials (RCTs) regarding the application of PRP from PubMed, EMBASE, Scopus, and the Cochrane Library. The data were analyzed using Review Manager 5.3. A total of nineteen RCTs (909 patients) were included. In contrast with conventional treatments, PRP achieved higher healing rate, higher percentage of area reduction, and smaller final area in vascular ulcers. However, the advantage disappeared in diabetic and pressure ulcers. Concerning adverse events, PRP showed lower incidence in the short term, but higher in the long term. No significant differences were found in ulcer closure velocity and healing time. Platelet-rich plasma effectiveness and safety in treating cutaneous ulceration depend on what is the ulceration etiology. For diabetic ulcers, PRP showed no satisfactory results suggesting that PRP may not be suitable for diabetic patients. However, PRP could be efficient and more beneficial for vascular ulcers and effects on pressure ulcers remain unclear. Thus, PRP option should be carefully considered for each patient in accordance with their ulceration etiologies. © 2019 Wiley Periodicals, Inc.