<b><i>Background:</i></b> In elderly patients with chronic myeloid leukemia (CML) responsive to imatinib, the incidence of clinically significant (CS) late chronic anemia is still unknown. <b><i>Materials and Methods:</i></b> To highlight this issue, we revised retrospectively 81 CML patients aged &#x3e;60 years treated at our Institution with front-line imatinib for at least 24 months in durable complete cytogenetic response (CCyR). CS late chronic anemia was defined as the presence of persistent (&#x3e;6 months) and otherwise unexplained Hb levels ≤10 g/dL, which occurred &#x3e;6 months from imatinib start. <b><i>Results:</i></b> A condition of CS late chronic anemia occurred in 22 out of 81 patients (27.2%) at different intervals from imatinib start. Seven out of 22 patients (31.8%) needed packed red cell transfusions during the follow-up. At diagnosis, patients who developed CS late chronic anemia were significantly older and had a lower Hb median level. Six out of 22 patients with CS late chronic anemia received subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 IU weekly: all 6 patients achieved an erythroid response. A significantly worse event-free survival (EFS) in patients with untreated CS late chronic anemia was observed (<i>p</i> = 0.012). <b><i>Conclusions:</i></b> CS late chronic anemia during long-term treatment with imatinib is a common complication in responsive elderly patients, with worse EFS if untreated. Results with EPO are encouraging, but larger studies are warranted to define its role.