Background: Warts are common benign epidermal lesions caused by human papillomavirus (HPV) infection. IgE is the classic anaphylactic antibody that mediates the most immediate allergic and anaphylactic reactions and works to produce immunity against parasites and intracellular pathogens like viruses. Tumor necrosis factor α (TNFα) is considered as a pro-inflammatory cytokine, which is responsible for many functions like causing of cytolysis of specific tumor cell lines. Objective: To study the level of the immunoglobulin E (IgE) and TNFα in the sera of patients suffering from warts resistant to cryotherapy. Patients and Methods: This study was a case control study that included 90 subjects divided into 2 groups, case group that included 45 patients with warts and control group that included 45 age and sex matched healthy controls. This study included patients suffering from warts after 2 weeks of the last session of cryotherapy after receiving 2 sessions at least. Laboratory tests included measurement of serum IgE and serum TNFα. Results: About half of the patients had plantar warts, 42.2% had common warts, and 6.7% had genital warts. Median TNFα and IgE serum levels in this study were significantly higher among cases in comparison with controls. No significant relation was reported between TNFα and IgE serum levels and number of warts, type of warts, site of warts or number of sessions. Conclusion: Serum levels of TNFα and IgE were significantly elevated in patients suffering from warts resistant to cryotherapy in comparison with healthy individuals.