Although the combination of lenalidomide and dexamethasone is effective therapy for patients with relapsed/refractory multiple myeloma, the influence of high-risk cytogenetic abnormalities on outcomes is unknown. This subanalysis of a large, open-label study investigated the effects of the most common unfavorable cytogenetic abnormalities detected by fluorescence in situ hybridization, del(13q), t(4;14), and del(17p13), in 130 evaluable patients treated with this regimen. Whereas patients with either del(13q) or t(4;14) experienced a median time to progression and overall survival comparable with those without these cytogenetic abnormalities, patients with del(17p13) had a significantly worse outcome, with a median time to progression of 2.22 months (hazard ratio, 2.82; P < .001) and median overall survival of 4.67 months (hazard ratio, 3.23; P < .001). Improved therapeutic strategies are required for this subgroup of patients. This study was registered at www.ClinicalTrials.gov as #NCT00179647.