Data comparing long-term outcomes in lenalidomide-treated and untreated patients with myelodysplastic syndromes (MDS) with del(5q) are limited. We evaluated clinical outcomes of 295 lenalidomide-treated patients from two clinical trials (MDS-003 and MDS-004) and 125 untreated red blood cell (RBC) transfusion-dependent patients with del(5q) Low- or Intermediate-1 (Int-1)-risk MDS from a large multicenter registry. Risk factors for acute myeloid leukemia (AML) progression and mortality were assessed using Cox proportional hazards models with left truncation to adjust for study entry differences between cohorts. Baseline characteristics were well balanced across cohorts, except for a higher RBC transfusion burden in lenalidomide-treated patients (median, 6 vs 2 units/8 weeks). Median follow-up was 4.3 years from first dose for lenalidomide-treated patients and 4.6 years from diagnosis for untreated patients. Two-year cumulative AML progression incidences were 6.9% (95% confidence interval (CI): 3.3-13.9) and 12.1% (95% CI: 7.0-20.3) and 2-year overall survival (OS) probabilities were 89.9% (95% CI: 84.1-96.0) and 74.4% (95% CI: 66.1-83.7), respectively. AML progression risk was similar in both cohorts (hazard ratio (HR) 0.969, P=0.930); however, lenalidomide treatment was associated with significant improvement in survival (HR 0.597, P=0.012), after adjusting for all other covariates. In conclusion, lenalidomide treatment does not increase AML progression risk, but instead confers a possible survival benefit in RBC transfusion-dependent patients with del(5q) Low- or Int-1-risk MDS.