In rare disorders, there are often no standard therapy recommendations. Patients with refractory disease may require novel experimental approaches. Applied as second- up to fourth-line treatment, lenalidomide (10-25 mg perorally on days 1-21 in a 28-day cycle) was used in our cohort of four adult patients with aggressive, multisystem and relapsing diseases. Complete and long-lasting remissions (more than 1 year, no maintenance therapy) were achieved in patients with Langerhans cell histiocytosis (11 cycles, combination with dexamethasone and etoposide, consolidated by allogeneic blood stem cell transplant) and plasma-cell Castleman disease (15 cycles, monotherapy). Mixed response with complete disappearance of brain infiltrates was reached in Erdheim-Chester disease (6 cycles, monotherapy) and gastrointestinal bleeding was well controlled in multiple angiomatosis (9 cycles, combination with thalidomide). For disease activity evaluation each patient underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography scan imaging, which was complemented by clinical and laboratory investigations.