Transdermal delivery of drugs offers many advantages compared to traditional drug delivery systems, including oral and injectable preparations. Due to their amphiphilic nature, lipid vesicles may serve as non-toxic penetration enhancers for drugs (1, 2). However, this approach is not very successful because of poor skin permeability, breaking of vesicles, drug leakage, aggregation and fusion of vesicles. To overcome problems of poor skin permeability, a novel vesicular system, transfersomes (ultradeformable lipid vesicles) were proposed for non-invasive delivery of drugs into deep skin strata or across Cisplatin-loaded protransfersome system was prepared and characterized for in vitro drug permeation, drug deposition and antitumor effect. A histopathological study and a genotoxicity study were also done. The skin permeation data of cisplatin from protransfersome gel formulation revealed 494.33 ± 11.87 mg cm -2 , which was significantly higher than that from the control plain drug solution in 0.9 % NaCl (p < 0.001). Untreated group of animals showed invasive moderately differentiated keratinizing squamous cell carcinoma (malignant stage). However, with cisplatin loaded protransfersome gel system simple epithelial hyperplasia (pre-cancerous stage) with no cancerous growth was observed. Also, a significant induction in micronucleus formation was found in the group that was treated with injectable intraperitoneal cisplatin preparation in 0.9 % saline as compared to the group treated with topical protransfersome gel formulation. The findings of this research work appear to support improved, site-specific and localized drug action in the skin, thus providing a better option for dealing with skin related problems like squamous cell carcinoma.