BACKGROUND: Basic and clinical research support the hypothesis that activation of the coagulation and inflammation pathways may affect cancer onset, but there is limited epidemiological data to support this. METHODS: We examined a large range of haemostatic and inflammation markers, including fibrinogen, in 19 303 male participants from three English cohorts followed for up to 30 years. After excluding the first 3 years of follow-up, 2908 incident cancers were accrued. Competing risk models were fitted to estimate rate ratios (RRs) for cancer incidence, adjusting for age and other confounders. RESULTS: Baseline white blood cell (WBC) count and circulating levels of fibrinogen, C-reactive protein (CRP), factor VII antigen (VIIa) and prothrombin fragment F1.2 were positively associated with risk of smoking-related cancers, particularly lung cancer. The magnitude of these associations was highest for persistently raised fibrinogen levels. There was, however, substantial confounding by smoking with risk being fully (WBC, CRP and VIIa) or partially (fibrinogen) removed after adjustment. The pooled RRs (95% confidence interval) per one standard deviation increase in fibrinogen levels before and after adjustment for smoking habits were 1.23 (1.12, 1.36) and 1.12 (1.05, 1.20), respectively. The fibrinogen associations were present only among current smokers at entry. The effect of smoking on smoking-related cancers was partly mediated by fibrinogen levels. CONCLUSIONS: Our results are consistent with elevated circulating levels of fibrinogen and F1.2 being predictors of risk of smoking-related cancers. Further research is necessary to clarify whether elevated levels of fibrinogen and F1.2 are causally relevant or simply correlates of the smoking-cancer association.