The prevalence of anemia in patients with heart failure (HF) increases according to disease severity as a consequence of renal insufficiency, cytokine production, plasma volume expansion, and/or malnutrition. B-type natriuretic peptide (BNP) has been recognized as a biochemical marker of ventricular dysfunction. The aim of this study was to evaluate the clinical significance of anemia in HF patients and furthermore, to investigate whether a significant correlation exists between anemia, BNP, and poor clinical outcomes in HF patients. We studied 185 consecutive HF patients. We assessed the occurrence of major adverse cardiac events (MACE) post hospital discharge. Anemia was defined as Hb concentrations <12.9 g/dl in men and <11.3 g/dl in women, respectively. Kaplan-Meier analysis revealed that anemia and high BNP levels (>259 pg/ml) were significantly associated with the occurrence of MACE. Multiple logistic analysis revealed that the most predictive independent risk factor for the occurrence of MACE was high BNP levels, followed by anemia (relative risk [RR] = 2.803 and 2.241, respectively). We divided the patients with or without anemia and high or low BNP levels into four groups according to their respective Hb and BNP levels. The hazard ratio for MACE in the group with anemia and high BNP levels was 10.3 in comparison to the group without anemia and with low BNP levels (P = 0.0002). Both anemia and high plasma levels of BNP are significantly and independently associated with the occurrence of MACE in HF patients; furthermore, the synergistic effect of anemia combined with high BNP levels significantly predicts an enhanced risk for MACE.