Background: The phase III MDS-005 study compared lenalidomide versus placebo in red blood cell transfusion-dependent (RBC-TD) patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS), ineligible/refractory to erythropoiesis-stimulating agents. Lenalidomide-treated patients were more likely to achieve transfusion independence (TI) ≥ 8 weeks (26.9% vs. 2.5%; P <.001) and hemoglobin increase ≥ 1.5 g/dL (19.4% vs. 2.5%) versus placebo. Patients and Methods: Patients were randomized 2:1 to oral lenalidomide 10 mg once daily or placebo once daily (both on 28-day cycles). Patients with creatinine clearance 40 to 60 mL/min were given lenalidomide 5 mg once daily. Health-related quality of life (HRQoL), a predefined secondary end point, was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 questionnaire at baseline, week 12, week 24, every 12 weeks thereafter, and at discontinuation. Results: At week 24, lenalidomide was associated with benefit versus placebo across all 5 preselected questionnaire scales (fatigue, dyspnea, global quality of life, physical functioning, and emotional functioning). After adjustment for baseline scores, only emotional functioning achieved significance (P =.047). Further improvement versus baseline was observed for patients who continued lenalidomide after week 24. In post hoc analyses, achievement of TI ≥ 8 weeks was associated with significant improvements across all scales (P <.01); an increase in hemoglobin level correlated with significant improvements in all scales at week 24, except emotional functioning (P <.05). Conclusion: Lenalidomide did not adversely affect HRQoL in RBC-TD patients with lower-risk non-del(5q) MDS and response to lenalidomide was associated with significant improvements in HRQoL. Health-related quality of life (HRQoL) was evaluated among red blood cell transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS) treated with lenalidomide (n = 160) or placebo (n = 79) in the phase III MDS-005 study. Lenalidomide did not worsen HRQoL; response to lenalidomide was associated with significant HRQoL improvement. Lenalidomide represents a treatment option for patients with lower-risk non-del(5q) MDS who are ineligible for or refractory to erythropoiesis-stimulating agents.