Abstract Deformable liposomes were prepared to investigate the effectiveness of dermal administration of methotrexate (MTX). The phospholipids used to prepare the liposomes were soybean lecithin (PC) or hydrogenated lecithin (HPC) and dipotassium glycyrrhizinate (KG) as surfactant. The lipid/KG ratio (w/w) was 2:1 and 4:1. Liposomes size, entrapment efficiency and MTX release through dialysis membrane were determined and the interaction between MTX and liposomes was investigated using differential scanning calorimetry. The MTX amount permeated through pig skin were three- to four-fold higher using liposomes containing KG compared to those from water solution or normal liposomes. No significant differences were observed between PC-KG liposomes and HPC-KG liposomes. At the end of the skin permeation assay using deformable liposomes, up to 50% of the administered dose was found in the skin. This capability depends on the self-regulating carrier deformability. These results suggest that liposomes containing KG may be of value for the topical administration of MTX in the treatment of psoriasis.