Background Mastocytosis is characterized by the accumulation and activation of mast cells in different organs, most commonly the skin. Miltefosine, a raft modulator, has recently been shown to inhibit the activation of mast cells and to reduce mast cell-driven skin inflammatory responses. Objectives To study the safety and efficacy of topical miltefosine treatment of skin lesions in patients with mastocytosis. Methods Thirty-nine adult patients with mastocytosis with skin involvement were treated in a double-blind, placebo-controlled, parallel trial with topical miltefosine and clobetasol for 2 weeks. Treatment areas were analysed for changes in skin lesions and symptoms following mechanical irritation using novel volumetric imaging techniques and quantitative histomorphometry. Results Miltefosine and clobetasol failed to reduce significantly weals and flare-type skin responses following mechanical provocation. Miltefosine showed a trend towards reducing the volume of weals. Clobetasol significantly decreased the volume of weals and the number of mast cells in the upper dermis. Treatment with miltefosine, but not with clobetasol, was often associated with eczematous skin irritation, which may, at least in part, be related to the formulation of miltefosine containing the potentially irritating alkanol propanediol as the vehicle. Conclusions Raft modulators such as miltefosine are promising candidates for novel therapeutic strategies in patients with cutaneous mastocytosis. Future studies should be performed with improved formulations using nonirritant vehicles.