INTRODUCTION: This report discusses a rare case involving a patient with high-risk (HR) Del(5q) myelodysplastic syndrome (MDS) who achieved a long-term response to lenalidomide after having received six cycles of azacytidine. The latter treatment led to the clearance of blast cells from the bone marrow (BM). CASE REPRESENTATION: As per current clinical practice, patients with HR MDS receive azacytidine continuously until the disease progresses or the occurrence of unmanageable side effects. However, in this case, the patient decided to interrupt hypomethylation therapy. Due to the patient's preference for oral therapy at home, the absence of blast cells, the ongoing need for transfusions, and a cytogenetic abnormality-predictive response to lenalidomide, the choice of the latter agent allowed for a sustained response lasting up to 68 months. CONCLUSION: Our observations suggest that further studies could explore the sequential use of azacytidine followed by lenalidomide after achieving BM blast clearance in patients with HR MDS with del(5q).