Introduction: Cutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE.Methods: Fifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.Results: One patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomide's withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed.Conclusion: Lenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal.Trial registration: ClinicalTrials.gov: NCT01408199. © 2012 Cortés-Hernández et al.; licensee BioMed Central Ltd.