Painful oral lesions in patients with cancer, HIV or aphthous ulcers can cause significant pain and discomfort. Those with oral mucositis (OM) resulting from high-dose chemotherapy or irradiation are the most at risk for painful lesions that lead to significant morbidity and mortality, decreased quality of life and increased economic costs. Numerous approaches have been taken to prevent and treat OM in the cancer patient but this condition remains a significant obstacle to cancer therapy. Small studies have been done in healing oral lesions arising from laser surgery and in wound healing but research is needed to support the use of polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair) in these clinical setting. The purpose of this paper is to review the benefit of polyvinylpyrrolidone-sodium hyaluronate gel, a topical oral mucosal barrier gel to prevent or diminish the pain of OM and other oral lesions. Primary resources in peer-reviewed journals, chapters in recognized textbooks and information from international and national oncology and dental medicine scientific meetings. Oncology patients receiving high-dose immunosuppressive therapy are the most at risk with painful OM. Current prevention and treatment options for OM have limited effectiveness. Although opioids are available for pain management, novel agents, to be used alone or in combination with other proven measures to decrease the severity and duration of OM, are emerging. Clinical studies in the use of polyvinylpyrrolidone-sodium hyaluronate to reduce the pain or disruption to the oral mucosa has merit. Few clinical trials or main publications have supported the use of this product. Robust randomized trials are needed to further support the clinical utility of this agent.