Iron homeostasis is dysregulated in primary myelofibrosis (PMF), given the high prevalence of anemia, need for red blood cell (RBC) transfusions, and disease-associated inflammatory state. We measured plasma hepcidin levels in 203 consecutive PMF patients at the time of first referral; hepcidin levels were significantly higher as compared to healthy controls (P < 0.0001), and were correlated with hemoglobin of <10 g/dL, RBC transfusion requirement, serum ferritin of >500 mg/L, higher dynamic international prognostic scoring system (DIPSS)-plus risk category, the presence of circulating blasts, age of >65 years, and leukocyte count of <4 3 10 9 /L. Increased hepcidin levels predicted for inferior survival independent of six out of the eight DIPSS-plus prognostic parameters (hazard ratio [HR] 5 1.8; P 5 0.02), but not when RBC transfusion requirement, hemoglobin of <10 g/dL, or increased serum ferritin were included in the Cox model. Multivariable analysis that considered the four overlapping prognostic variables revealed that increased hepcidin (HR 5 1.9; P 5 0.03) and increased ferritin (HR 5 2.3; P 5 0.04), but not hemoglobin of <10 g/dL or RBC transfusion requirement, independently retained their significance for predicting survival. Accordingly, increased levels of both hepcidin and serum ferritin (seen in 29% of patients) predicted inferior survival independent of DIPSS-plus or increased inflammatory cytokine levels (HR 5 2.4; P 5 0.002), and could be considered in future prognostic models for PMF. Am. J.