The present study aimes to evaluate the possibility of using different alginate-based matrix system for transdermal delivery of methotrexate. Low-dose methotrexate is an inexpensive, effective and widely used treatment as immunosuppressant drug for inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis and as anticancer drug. TG, DSC and FT-IR studies have been used to highlight the degree of incorporation of the active substance in the membrane and the possible interactions between the drug and the polymer.Transdermal drug delivery permits the use of a relatively potent drug with minimal risk of systemic toxicity and avoids the gastrointestinal degradation and hepatic first-pass metabolism [1]. Polymers are one of the major chemical compounds which find an important place in the field of engineering, medicine and pharmaceutical field these days and the major focus has been on the biodegradable ones, alginates in particular [2]. Alginates are polysaccharides found in the brown algae [3]. Alginates available for industrial use include sodium alginate, potassium alginate, mixed sodiumcalcium alginate, salt of alginic acid and propylene glycol alginates. They are natural gums and offer advantages over synthetic polymers as they form hydrogels and they are non-toxic, biocompatible, biodegradable, less expensive and easily available. All these advantages make alginates very useful material for biomedical applications, especially for controlled delivery of drugs and other biologically active compounds.