The present study aimed to quantify the magnitude of the systemic inflammatory response, measured by C-reactive protein (CRP) and albumin, and its relationship with common serum biochemical measures of iron status including total iron, transferrin, transferrin saturation, and ferritin. Retrospective interrogation of laboratory computer databases at 4 centers between 2006 and 2011 provided results from patients in which serum CRP and albumin had been measured together with iron studies (iron, transferrin, and transferrin saturation, n = 16,522) and ferritin (n = 7,226). Analyte results were categorized into groups according to CRP and albumin. When those groups with CRP <10 mg/L and albumin >35 g/L, CRP 11–80 mg/L and albumin 25–35 mg/L, and CRP >80 mg/L and albumin <25 g/L were compared, the median serum total iron was 15.0, 7.0, and 3.0 μmol/L, respectively (P< 0.001), an overall reduction of 80%. The median serum transferrin concentration was 2.6, 2.0, and 1.3 μmol/L respectively (P< 0.001), an overall reduction of 50%. The median transferrin saturation was 23%, 13%, and 10% respectively (P< 0.001), an overall reduction of 56%. The median serum ferritin was 77, 173, and 445 μg/L respectively (P< 0.001), an overall increase of 578%. The present study quantifies the impact of the systemic inflammatory response on serum measures of iron status. This association should be taken into account when measures of iron status are requested and interpreted to prevent misdiagnosis.