Anemia is becoming recognized as a substantial problem for patients with cancer who are not receiving chemotherapy. Recently, darbepoetin alfa has been shown to provide significant clinical benefits in this patient population. This analysis assesses the effect of change in hemoglobin levels on health-related quality of life (HRQOL) in these patients. Eligible patients had anemia (hemoglobin </= 11 g/dL), had nonmyeloid malignancy, and had not received cytotoxic chemotherapy or radiation therapy </= 8 weeks before the study. Fatigue and other HRQOL outcomes were measured using the Functional Assessment of Cancer Therapy (FACT) General and Fatigue subscales, the Brief Symptom Inventory depression and anxiety subscales, and numeric rating scales of energy, activity, and overall health. Improvements in hemoglobin were significantly associated with reductions in fatigue (P < 0.001), improvements in functional (P < 0.0001) and physical (P = 0.001) well-being, depression (P = 0.023), anxiety (P = 0.022), and global ratings of energy (P = 0.0004), activity (P = 0.0008), and overall health (P = 0.003). Clinically meaningful improvements in fatigue (defined as an increase in FACT-Fatigue subscale score of >/= 3 points) were significantly (P < 0.05) associated with improvements in functional, physical, and emotional well-being, depression, anxiety, and global ratings of energy, activity, and overall health. In summary, an increase in hemoglobin was associated with a decrease in fatigue in patients with anemia associated with nonmyeloid malignancies who were not receiving chemotherapy.