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Several studies have looked into the effectiveness of bleomycin treatment for warts using various injection methods, such as intralesional injection, multiple puncture technique, jet injection, and moonlet needle prick method, in various concentrations and doses. However, injection methods have been linked to acute pain and bleeding. The purpose of this study is to examine the efficacy of microneedling combination with topical bleomycin and cryotherapy in the treatment of resistant warts on the hands and feet. This randomized clinical trial, conducted at Sina Hospital in Tabriz, involved 90 patients with treatment-resistant warts on their hands and feet. Treatment measures were repeated every two weeks in treatment-resistant patients who did not react to four cryotherapy sessions or whose lesions remained stable for six months. Each wart lesion was randomly assigned to one of two treatment groups: topical bleomycin with microneedling or cryotherapy. The effectiveness of the treatment in weeks 2, 4, 6, and 8 with PGA and PaGA, the amount of clearance, and side effects were evaluated in each session and the 8th week. Pain during therapy was assessed using a visual analog scale (VAS) ranging from 0 to 10. The patients' mean age was 33.65 ± 12.24 years, with 63.3% being female. A total of 186 resistant wart lesions were treated, with 98 (52.7%) situated in the palmar region and 88 (47.3%) in the plantar region. In palm lesions, the bleomycin micro-needling group had a considerably greater clearance rate than the cryotherapy group (86.4% vs. 61.9%; p = 0.001). In foot lesions, the bleomycin microneedling group had a greater clearance rate than the cryotherapy group, although there was no statistically significant difference (69.6% vs. 54.2%; p = 0.209). In the eighth week following the intervention, the number of lesions and the diameter of warts on the palms and feet decreased significantly in the bleomycin microneedling group when compared to the cryotherapy group. Bleomycin microneedling had no adverse effects; however, in patients undergoing cryotherapy, local pain, blisters, and scars were noted. Bleomycin microneedling has a higher therapeutic efficiency than cryotherapy for treating refractory hand and foot warts, and it removes lesions more effectively. In addition, this therapeutic method is safer and has fewer side effects than cryotherapy., Competing Interests: Declarations. Ethical approval: This study was approved by the Ethics Committee of Tabriz University of Medical Sciences, following the ethical principles of the Helsinki Declaration and Good Clinical Practices (Protocol number, IR.TBZMED.REC.1401.1004, and was prospectively registered at IRCT.ir, clinical trials registry, with identifier number: IRCT20221109056452N1). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)