Blacks have been consistently observed to have higher serum ferritin (SF) concentrations than whites; however, few studies have attempted to explore why this difference exists. 3,554 non-Hispanic white (NHW) and non-Hispanic black (NHB) male subjects, aged 20-65 years, were selected from the third National Health and Nutrition Examination Survey (NHANES III) to determine the possible factors that may contribute to the observed black-white SF difference. Results of multiple regression analyses showed that age, body mass index (BMI), % energy from carbohydrate and fat, calcium intake, serum total protein, serum α-carotene, mean cell volume (MCV), iron binding capacity (TIBC) and γ glutamyl transferase (GGT) were significantly associated with SF concentration. When the final regression model was run after excluding subjects with abnormal serum total protein, TIBC and GGT levels, the SF difference dropped to 3.95µg/L (initial difference=37.06µg/L) between NHWs and NHBs. The results suggest that the noted black-white SF difference is a result of factors including overall nutrition and health, iron status and hepatic well-being. Higher SF, low Hb and reduced TIBC level observed in blacks are consistent with the definition of anemia of chronic disease (ACD). Future investigations are needed to confirm the role of ACD in the black-white SF difference. We also examined different sub-populations to investigate whether the likelihood and magnitude of SF elevation in regard to acute inflammation and hepatitis C are different between NHBs and NHWs by using logistic regression analyses. Compared to NHWs, NHBs had a 2.239-fold (95% CI, 1.333 to 3.760) greater risk to have elevated SF in regard to acute inflammation, and had significantly higher odds ratios of having elevated SF per unit change in C-reactive protein (CRP), white blood cell count (WBC), serum albumin, lymphocyte and platelet count. However, no significant results were found for hepatitis C. The results indicated that NHWs and NHBs had different patterns of iron accumulation in regard to acute inflammation. Further elucidation is needed about how ferritin regulation is perturbed in diseases, and whether increased stored iron plays a role in different clinical outcomes and drug response. Adequately powered studies are needed to further investigate the relationship between stored iron and hepatitis C host response.