Background: Basal cell carcinoma is the most common malignancies of the skin. Numerous modalities of treatment are available. Podophyllin is an antimitotic and caustic agent that has been used in treatment of genital warts. Objective: To test the effectiveness and safety of topical 25% podophyllin in treatment of basal cell carcinoma. Patients and Methods: Thirty eight patients with basal cell carcinoma enrolled in this open labeled interventional study that had been enrolled in Department of Dermatology-Baghdad Teaching Hospital, Baghdad, from January 2010 to October 2011. History and physical examination was performed to all patients regarding all demographics detail related to the disease. Exclusion criteria: were pregnancy, recurrent tumors, aggressive deep subtypes, morpheaic type, and size more than 2 cm2 in diameter. Biopsies for all patients were done for histopathological examination at the first visit, and after clinical cure of the lesions. Lesions were treated with 25% topical podophyllin solution once weekly for 6 weeks. Follow up after clinical cured was done every 3 months up to 18 months to recording any sign and symptom of recurrent. Results: Thirty five patients with basal cell carcinoma completed the study: 28 (80%) males and 7(20%) females with males to females ratio 4:1, their ages ranged from 30 – 87 (64.114 ± 12.68) years, and the duration of the disease ranged from 2 months to 30 years (6.88. ± 4.83) years. The size of lesions ranged from 0.8 – 1.9 (1.454 ± 0.239) cm. The total podophyllin applications number ranged from 2 – 6 (4.65 ± 1.055) sessions. The total numbers of treated lesions were 100 lesions: 64 (64%) nodular, 31(31%) pigmented, 3(3%) Basosquamous, and 2 (2%) superficial. Ninety six (96%) lesions in 32 patients showed complete cure with 2 – 6 sessions, while 4 lesions in 3 patients showed partial response with 6 sessions. Biopsy from 21 cured lesions in 21 patients showed complete clearness apart from one with residual malignant cells. All the patients did not show clinical recurrence, during the follow up period up to 18 months. Inflammatory reactions were noted in all treated lesions as redness, edema and juicy skin 36 – 72 hours after topical podophyllin applications. After 3 – 5 days, the reaction became more exaggerated and ulceration developed, ended with crust formation. No evidence of systemic side effects was seen and this had been confirmed clinically and by laboratory during the sessions and one month later. Minimal or no scarring was noticed. Conclusions: Topical 25% podophyllin solution is a new, effective therapeutic modality in treatment of basal cell carcinoma which gives 96% cure, and it is highly recommended as alternative therapy in all type of basal cell carcinoma, single and multiple and for all ages especially for elderly patients and those who have surgeries phobia.