This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 RBC transfusion-dependent patients with IPSS Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes (MDS). Patients received lenalidomide 10 mg/day days 1-21 (n = 69) or 5 mg/day days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up 1.55 years), with 60%-67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q MDS. This trial was registered at www.clinicaltrials.gov as #NCT00179621.