OBJECTIVE: This was an open-label study to asses the association of changes in hemoglobin with changes in health related quality of life (HRQOL) in patients treated with darbepoetin alfa. METHODS: Originally, 81 chronic kidney disease (CKD) patients not on dialysis and naive to erythropoiesis stimulating agents (ESA) were randomly assigned into two open-label groups (3 : 1). As a majority of control group patients opted out of control status, this study reports on the single arm study analysis that was performed on the 48 patients who received the drug through week 16. Sixty-two patients received once-weekly darbepoetin alfa in addition to conservative management for CKD. Instruments that measured general (SF-36, FACTanemia, FACT-fatigue, ADL and IADL) and disease specific (KDQOL) HRQOL domains were administered at baseline and after 8, 16, and 24 weeks. RESULTS: Compared to baseline values, mean HRQOL subscales were significantly improved in the treatment group at 16 weeks (p textless 0.05 for SF-36 physical function; p textless 0.001 for SF-36 vitality, FACT anemia and FACT fatigue scales). At week 16, the SF-36 mean increase for 48 treatment patients in the Vitality Subscale Score was 14.9 (SD 3.2) and the mean increase in the KDQOL Burden of Kidney Disease Subscale was 5.5 (SD 3.3). Multivariate regression analysis demonstrated a statistically significant association (p textless 0.05) between hemoglobin levels and higher HRQOL scores on several physical function, energy and fatigue scales. CONCLUSION: Improvements in hemoglobin in CKD patients not on dialysis were associated with statistically significant (p textless 0.05), clinically meaningful (textgreater 5 points) HRQOL improvements on scales measuring physical activity, vitality and fatigue. Our study did not show an association between increased hemoglobin levels and other aspects of HRQOL, such as those relating to emotional status, sexual activity or cognition. The interpretation of our results is limited by the lack of a control arm to assess whether conservative therapy for CKD, in the absence of ESA administration, would have a comparable effect on patients' HRQOL scores. Further research needs to examine whether other aspects of HRQOL improve with anemia treatment, in the same way as those aspects of HRQOL more closely related to physical activity and fatigue.