Fludarabine-based therapy is widely approved as a first-line treatment for chronic lymphocytic leukemia (CLL). This treatment is occasionally associated with prolonged myelosuppression. We herein describe the cases of CLL who underwent fludarabine, cyclophosphamide and rituximab (FCR) therapy. Bone marrow examinations performed during periods of prolonged myelosuppression revealed definite myelodysplastic changes in the myeloid and erythroid lineages. G-banded karyotyping analyses revealed cytogenetic abnormalities. The patients were diagnosed with therapy-related myelodysplastic syndrome (t-MDS). Further administration of cytotoxic therapy was aborted, and no progression of t-MDS was recorded throughout the follow-up period in either case. In these cases, the t-MDS was characterized by a short latency interval and a benign clinical course. Because typical t-MDS with aggressive outcomes also occurs during prolonged myelosuppression, the transition of the clinical course in this setting should therefore be carefully watched.