Prior case–control studies reported that levels of the soluble form of the endothelial protein C receptor (sEPCR) were strongly controlled by the PROCR 6963A/G polymorphism and higher levels were a risk factor for venous thromboembolism (VTE). We sought to prospectively examine the association of sEPCR and the 6963A/G polymorphism with the incidence of VTE. The Longitudinal Investigation of Thromboembolism Etiology (LITE) pooled data from the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) Study on men and women aged ≥45 years. A nested case–control study of 458 incident VTE and 1038 controls was performed. sEPCR levels were distributed trimodally according to 6963A/G polymorphism. Adjusting for age, sex and race, there was no overall association between sEPCR level and VTE: odds ratio (OR) [95% confidence interval] for highest versus lowest quartile = 1·17[0·86–1·59]. However, higher sEPCR was associated with VTE in non-whites (OR = 1·84[1·05–3·22]) and women (OR = 1·51[1·01–2·26]). The 6963A/G polymorphism was not associated with VTE risk (OR = 0·93[0·70–1·25]). In conclusion, sEPCR levels and the PROCR 6963A/G polymorphism were not associated overall with increased risk of VTE.