Lenalidomide and hypomethylating agents (HMAs) azacitidine and decitabine are approved for treating myelodysplastic syndromes (MDS), but optimal sequencing is unclear. Adults with MDS were identified from a US payer claims database (Inovalon MORE2 Registry) to compare outcomes with lenalidomide followed by HMA (LEN-HMA) or HMA followed by lenalidomide (HMA-LEN). There were 96 patients who received LEN-HMA and 89 who received HMA-LEN. LEN-HMA-treated patients had a longer time to second treatment discontinuation (29.0 vs. 19.0 months, p=.009; adjusted hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.29-0.91, p=.023). LEN-HMA-treated patients had a longer median time to insurance disenrollment (22.4 vs. 16.1 months, p<.001; adjusted HR 0.64, 95% CI: 0.44-0.92, p=.017), used as a proxy for survival. Longer treatment duration and survival with LEN-HMA support first-line use of lenalidomide in MDS in sequence with HMAs.