BACKGROUND Intralesional antigen immunotherapy represents a promising therapeutic approach for the treatment of different types of warts, particularly if multiple and/or recalcitrant. OBJECTIVE to investigate the efficacy and safety of combined cryotherapy with intralesional purified protein derivative (PPD) immunotherapy in the treatment of multiple common warts. METHODS Fifty patients were randomly divided into two groups (25 patients each): Group A: receiving intralesional PPD immunotherapy for the largest wart, while group B: receiving cryotherapy for all warts plus intralesional PPD for the largest wart. Treatments were performed every 2 weeks for a maximum of four sessions. Photographs were taken at baseline and at each visit and clinical response was evaluated by the reduction in number and size of warts. Adverse effects were recorded. RESULTS There was a significant reduction in size and number of warts in both groups (P < .001), with no significant difference between the two groups. Complete clearance of the lesions was observed in 48% of patients in group A and 44% in group B (P = .39). Higher rates of near complete/complete response were achieved after fewer sessions (2, 3 sessions) in group B (P = .002). Blistering was common after cryotherapy. Higher rate of hypopigmentation was noticed after combined treatment than after PPD monotherapy (56%, 8% respectively; P < .001), which resolved gradually. CONCLUSIONS Both intralesional PPD alone and combined cryotherapy with PPD are safe and effective in clearing of common warts. Cryotherapy may be a successful adjunct to intralesional PPD immunotherapy that helps in reducing the number of treatment sessions.The study protocol was registered at ClinicalTrials.gov with ID: NCT04288817.