Background: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp™) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. Methods: In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin ≤11.0 g/dL) were randomly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks. The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions, the primary endpoint. Patients were also assessed for hemoglobin concentration (i.e., hematopoietic response), adverse events, antibody formation to darbepoetin alfa, hospitalizations, Functional Assessment of Cancer Therapy (FACT)–Fatigue score, and disease outcome. Efficacy endpoints were assessed using Kaplan–Meier analyses, Cox proportional hazards analyses, and chi-square tests where appropriate. All statistical tests were two-sided. Results: Patients receiving darbepoetin alfa required fewer transfusions (27% versus 52%; mean difference = 25%; 95% confidence interval [CI] = 14% to 36%; P<.001), required fewer units of blood (0.67 versus 1.92; mean difference = 1.25, 95% CI = 0.65 to 1.84; P<.001), had more hematopoietic responses (66% versus 24%; mean difference = 42%; 95% CI = 31% to 53%; P<.001), and had better improvement in FACT–Fatigue scores (56% versus 44% overall improvement; 32% versus 19% with ≥25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P = .019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. Conclusions: Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.