The increasing number of effective agents allows rescue therapy of patients with light-chain (AL) amyloidosis refractory to ≥2 previous treatments. Lenalidomide is effective in this disease and its toxicity profile encourages its use in salvage regimens. All the patients with AL amyloidosis refractory to both melphalan and bortezomib referred to our center between July 2007 and July 2009 were treated with the combination of lenalidomide and dexamethasone. Twenty-four consecutive patients were enrolled. Seventy-nine percent were also refractory to thalidomide. Two patients died before evaluation of response, and 50% experienced severe adverse events. Survival was significantly shorter in subjects with troponin I >0.1 ng/mL and in patients diagnosed <18 months before treatment initiation. Hematologic response was observed in 41% of patients and prolonged survival (median 10 months vs. not reached, P = 0.005) independently from troponin I concentration and from pre-treatment disease duration. Salvage therapy beyond second line of treatment can improve survival in AL amyloidosis and lenalidomide plus dexamethasone is a valuable option in this setting.