Epidemiologic studies linking high serum iron with cancer risks are limited and inconclusive, despite evidence implicating body iron in human carcinogenesis. A cohort of 309,443 adults in Taiwan who had no history of cancer had serum iron levels tested at the time of recruitment (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008). Initially measured iron levels were associated with subsequent cancer risk by linking individuals with the National Cancer Registry and National Death File. HRs were calculated by the Cox model. One third of males (35%) and one fifth of females (18%) had high serum iron (!120 mg/dL), which was associated with a 25% increase in risk for incidence of all cancers [HR, 1.25; 95% confidence interval (CI), 1.16-1.35] and with a 39% increase in risk for mortality from all cancers (HR, 1.39; 95% CI, 1.23-1.57). The relationship between serum iron and cancer risk was a J-shaped one, with higher cancer risk at both ends, either at lower than 60 mg/dL or higher than 120 mg/dL. At the higher end, cancer risk increased by 4% for every 10 mg/dL increment above 80 mg/dL, showing a dose-response relationship, with 60 to 79 mg/dL as a reference level. In a sensitivity analysis, the increases in risk were still observed after the first 5 years of cancer cases were excluded. Liver cancer risk was increased in HBV (À) non-hepatitis B carrier (3-fold) and HBV (þ) hepatitis B carrier (24-fold). Lifestyle risks such as smoking, drinking, or inactivity interacted synergistically with high serum iron and significantly increased the cancer risks. The liver (HR, 2.49; 95% CI, 1.97-3.16) and the breast (HR, 1.31; 95% CI, 1.01-1.70) were the two major cancer sites where significant cancer risks were observed for serum iron either !120 mg/dL or !140 mg/dL, respectively. This study reveals that high serum iron is both a common disorder and a marker of increased risk for several cancers. Cancer Res; 74(22); 6589-97. Ó2014 AACR.