• Background: Wart management poses a persistent challenge despite existing numerous therapeutic modalities. Human papilloma virus (HPV) vaccines have shown promising efficacy in the treatment of warts. • Objective: To assess the efficacy of intralesional quadrivalent versus bivalent HPV vaccines in the treatment of multiple recalcitrant warts. • Methods: The study included 50 patients with multiple recalcitrant warts who were randomly assigned to 3 groups. The first group (20 patients) received intralesional injection of 0.1 ml of quadrivalent vaccine, the second group (20 patients) was intralesionally injected with 0.1 ml of bivalent vaccine, and the third group (10 patients) received 0.1 ml of intralesional saline. Injections were done at 2-week intervals until complete clearance or for a maximum of 5 sessions. • Results: Quadrivalent vaccine was associated with a statistically higher response rate (90%) compared to both bivalent vaccine (30%) and saline (0%) groups (P= 0.001). All reported side effects in the treatment groups were mild, transient and tolerable. No recurrence of warts was observed during the 6-month follow-up period. • Conclusions: Bivalent and quadrivalent HPV vaccines seem to be promising, well-tolerated therapeutic options for the treatment of multiple recalcitrant warts, with statistically significant superiority of the quadrivalent vaccine.