Miltefosine is currently marketed for treatment of skin metastasis of breast cancer and leishmaniasis. The mechanism of action is not fully understood, however, miltefosine is considered to be a prototype lipid raft modulator. The compound was shown to inhibit anti-IgE induced histamine release from human skin mast cells. After topical treatment it reduced skin reaction in allergic human volunteers undergoing a skin prick test. The aim of this study was to test whether miltefosine could also modify T-cell signalling and whether the drug may be useful for the treatment of atopic dermatitis. Miltefosine (20microM) inhibited T-cell proliferation by >50% in the mixed leukocyte test. In the toluene diisocyanate induced ear swelling test, miltefosine, administered topically as 2 and 6% solution or orally, attenuated ear swelling reaching 70% of the effect of dexamethasone at 100mg/kg p.o. (P<0.01). The ear tissue content of the cytokines IL1beta, IL4 and IL6 was also reduced reaching 56% or 52% reduction of IL1beta (P<0.01) after 2% topical or 100mg/kg p.o. Miltefosine significantly attenuated the allergic sensitization in the model of ovalbumin induced delayed-type hypersensitivity in mice. In a model of toluene diisocyanate induced scratching a significant (P=0.0047) reduction of scratching from 47 to 6 bouts was achieved with 100mg/kg p.o. The data indicate that miltefosine modulates T-cell function in models for Th1 and Th2 related activity. This profile opens up the possibility for the treatment of T-cell related allergic diseases with a novel class of lipid raft modulator drugs such as miltefosine.