Purpose: This phase II study assessed clofarabine monotherapy in older adults (≥ 60 years of age) with untreated acute myeloid leukemia (AML) and at least one unfavorable baseline prognostic factor. Patients and Methods: Clofarabine was administered intravenously for 5 days at 30 mg/m2/d during induction and 20 mg/m2/d during reinduction/consolidation (six cycles maximum). The primary end point was overall remission rate (ORR; ie, complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Results: In 112 evaluable patients who were treated (median age, 71 years; range, 60 to 88 years), the ORR was 46% (38% CR, 8% CRp). ORR by unfavorable prognostic factor was 39% for patients ≥ 70 years of age; 32% for Eastern Cooperative Oncology Group (ECOG) performance status 2; 51% for antecedent hematologic disorder; 54% for intermediate karyotype; 42% for unfavorable karyotype; and 48%, 51%, and 38% for one, two, and three risk factors, respectively. The median disease-free survival was 37 weeks (95% CI, 26 to 56 weeks). Median duration of remission was 56 weeks (95% CI, 33 to not estimable). The estimated median overall survival was 41 weeks (95% CI, 28 to 53 weeks) for all patients, 59 weeks for patients with CR/CRp, and 72 weeks for patients with CR. The 30-day all-cause mortality was 9.8%. The most common non-laboratory drug-related toxicities (≥ 20% patients) were nausea, febrile neutropenia, vomiting, diarrhea, rash, and fatigue. Conclusion: Clofarabine is an active agent with acceptable toxicity in patients age 60 years or older with untreated AML who have at least one unfavorable prognostic factor. ORR did not seem affected by the presence of multiple unfavorable prognostic factors. © 2010 by the American Society of Clinical Oncology.