Proliferative verrucous leukoplakia (PVL) is a unique oral white lesion in which human papillomavirus (HPV) may play a role. PVL behaves far more aggressively than other forms of leukoplakia with a high rate of recurrence after surgical excision, and relentless progression to verrucous hyperplasia and to verrucous or squamous cell carcinomas. The treatment of PVL is usually by surgery, but there is often early recurrence. This study was an open trial of surgery in 25 patients with oral HPV-positive PVL, compared with combined therapy using surgery and methisoprinol in another group of 25 patients with oral PVL. Six months postoperatively there was a significant difference, with 18 recurrences in the patients treated by surgery alone compared to only two recurrences in the patients treated also with methisoprinol (isoprinosine or inosine pranobex), a synthetic agent with immunomodulatory properties and some antiviral activity against HPV. Eighteen months postoperatively there were no further recurrences in the patients treated by surgery alone but another two recurrences in the patients treated with methisoprinol. Overall, by 18 months follow-up, there were 18 recurrences in the group treated by surgery alone, compared with four in those also receiving methisoprinol. The use of this antiviral agent appeared to offer a significant enhancement to the surgical management of PVL.