There is strong evidence from observational studies suggesting serum C-reactive protein (CRP) is associated with cardiovascular and all-cause mortality. However, less is known about whether there are differences in the association of CRP with all-cause or cause specific mortality by sex, smoking, body mass index (BMI), or physical activity. We aimed to investigate these interactions and also investigate and compare the association of CRP and other inflammation markers (i.e., fibrinogen and leukocyte count) with all-cause and cause-specific mortality. Men and women aged 40-79 were recruited in 1993-1997 in the EPIC-Norfolk cohort study. A total of 16,850 participants with high-sensitivity assayed CRP data who had no known cancer, myocardial infarction and stroke at baseline were entered in the analysis to test the association of CRP, fibrinogen and leukocyte count with risk of all-cause and cause specific mortality. A total of, 2,603 all-cause deaths (1,452 in men) including 823 cardiovascular and 1,035 cancer deaths, were observed after 231,000 person-years of follow-up (median 14.3 years). CRP was positively associated with risk of all-cause, cardiovascular, and non-cancer non-cardiovascular mortality independent of established risk factors. The hazard ratio of all-cause mortality (95 % CI) for participants with CRP in the range of 3-10 and >10 mg/l (vs. <0.5 mg/l) was 1.56 (1.26-1.93) and 1.87 (1.43-2.43) respectively in men and 1.34 (1.07-1.68) and 1.98 (1.50-2.63) in women. The association was less positively graded in women with the increased risk being significant only at higher levels of the CRP distribution. The association persisted in never smokers and did not vary by levels of BMI or physical activity. Although fibrinogen and leukocyte count were also positively associated with mortality risk, only CRP remained a significant predictor of mortality when the inflammation markers were adjusted for one another in multivariable models. Serum CRP levels were a long-term predictor of risk of cardiovascular and non-cardiovascular mortality independent of known risk factors, fibrinogen, and leukocyte count.