OBJECTIVES: To understand the current extent of anemia in HIV/AIDS patients and its impact on health-related quality of life (HRQL). METHODS: HIV/AIDS patients >18 years of age were recruited from STD/HIV clinics across the US throughout 2003 to complete self-administered questionnaires. Clinical status was assessed with questions on medical history and HIV disease and treatment, while HRQL was quantified using the SF-8. RESULTS: In total, 2044 patients were recruited; 498 (24%) reported that they experienced anemia (as indicated by a health care provider) as a side effect of medication within the previous month. Although anemic and non-anemic individuals were similar in age, gender, HIV viral load, and use of AZT, NRTI and NNRTI treatment, anemic patients were more likely to be non-Caucasian, have a lower CD4 count, and more likely to be on PIs. Similarly, anemic patients were significantly more likely to have anxiety, depression, and cardiovascular comorbidities (p<0.0001). Further, anemic patients had significantly lower scores vs. non-anemic patients on the mental and physical component summary scores of the SF-8 (mental: 38.2+11.6 anemic vs. 42.9+11.9 non-anemic p<0.0001; physical: 40.1 + 10.0 anemic vs. 45.5+10.4 non-anemic p<0.0001). There was a significantly higher prevalence of great difficulty or inability to perform daily work among the anemic patients (33% anemic vs. 19% non-anemic, p<0.0001). In a multivariate logistic regression model controlling for relevant demographic, disease and treatment characteristics, anemic patients experienced significantly lower levels of mental (-4.1 SF-8 MCS score, p<0.001) and physical (-4.9 SF-8 PCS score, p<0.001) well-being than non-anemic patients. CONCLUSION: Independent of AZT use, anemia is prevalent in the HIV/AIDS population in the HAART era. Controlling for relevant confounders, anemia is independently associated with a diminished HRQL.