Background <p>Anemia is highly prevalent among hospitalized older adults and is associated with increased morbidity and mortality. Hepcidin is a liver-derived hormone that reduces iron availability and contributes to anemia. As the key regulator of iron metabolism, hepcidin is hypothesized to promote anemia development through inflammation-mediated pathways. However, the role of hepcidin in different types of anemia among frail, acutely hospitalized older patients remains poorly understood. The present study aimed to investigate the relationship between circulating hepcidin levels and markers of inflammation, anemia, frailty, comorbidity, and kidney function in a cohort of acutely hospitalized older patients.</p> Methods <p>Data from 1,030 patients aged ≥ 65 years from the Copenhagen PROTECT study were analyzed. Plasma hepcidin and interleukin-6 (IL-6) were measured using immunoassays, while standard biochemical markers, including hemoglobin and C-reactive protein (CRP), were assessed by routine clinical platforms. Anemia was defined according to WHO criteria. Frailty and comorbidity were evaluated using the Clinical Frailty Scale and the age-adjusted Charlson Comorbidity Index (CCI), respectively. Kidney function was determined by estimated glomerular filtration rate (eGFR). Correlations were examined using Pearson or Spearman methods depending on distribution and post hoc analyses included subgroup comparisons stratified by frailty and CCI strata. In exploratory multivariable analyses, hemoglobin was associated with hepcidin, inflammation, renal function, frailty, and comorbidity.</p> Results <p>Anemia was present in 48% of patients, with 10% of these displaying moderate-to-severe anemia. Hepcidin levels were significantly lower in patients with severe anemia compared to non-anemic patients. Notably, no consistent correlation was found between hepcidin and hemoglobin overall. Median hepcidin was 60.1 ng/mL [IQR 21.8–126.2] and showed moderate positive correlations with CRP (<i>r</i> = 0.48) and IL-6 (<i>r</i> = 0.47) (both <i>p</i> &lt; 0.001). Hepcidin levels were lower in frail patients and varied modestly across comorbidity strata.</p> Conclusions <p>In this cohort of acutely admitted older medical patients, hepcidin was moderately associated with inflammation and showed modest associations with frailty, comorbidity, and anemia severity. Although no overall correlation was found between hepcidin and hemoglobin, patients with more severe anemia showed lower hepcidin levels. These findings suggest that inflammation is the primary driver of hepcidin regulation in this population.</p> Trial registration <p>The study was approved by the Regional Ethics Committee of Copenhagen and Frederiksberg (H19039214) and the Danish Data Protection Agency (P2019239).</p>