Fibrinogen levels have been reported in cohort and case-control studies to be positively related to the development of coronary heart disease. This report presents the distribution and determinants of fibrinogen in women enrolling in a 3-year randomized trial of hormone replacement therapy (HRT), the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. Fasting plasma fibrinogen levels were measured in 874 postmenopausal women, aged 45 to 65 years, who had not used HRT for at least 3.5 months. Mean (±SD) fibrinogen level was 2.83±0.45 g/L. There was a significant positive association between fibrinogen and age (P=.03). Significantly higher (P<.005) fibrinogen levels were seen in current smokers versus nonsmokers (2.94 versus 2.81 g/L), in women who reported consuming fewer than 12 alcoholic drinks in the 12 months before the baseline visit versus higher consumption (2.90 versus 2.79 g/L), and in women who reported never versus ever having used HRT (2.90 versus 2.77 g/L). Self-reported leisure time physical activity (LTPA) was negatively associated (P=.0001) with fibrinogen levels as follows: inactive (2.84 g/L), light (2.89 g/L), moderate (2.80 g/L), and heavy (2.60 g/L), with significantly (P=.0001) lower levels in women who reported heavy LTPA versus each of the other categories and in women reporting moderate versus light LTPA. A strong positive correlation was found between fibrinogen and body mass index (BMI) (r=.32; P<.0001). In a model that included age, smoking, alcohol intake, prior HRT, LTPA, and BMI, LTPA was no longer a statistically significant predictor of fibrinogen level, while associations with other variables remained significant. Fibrinogen was positively associated (P<.001) with waist, hip, and thigh girths and waist-to-hip ratio, but these relationships were no longer significant after adjustment for BMI. In contrast, negative associations with HDL cholesterol (r=-.25; P<.001) and positive associations with LDL cholesterol (r=.16; P<.001) remained significant (P<.01 and P<.05, respectively) after simultaneous adjustment for age, smoking, alcohol, prior HRT, LTPA, and BMI. Statistically significant univariate associations between fibrinogen and triglycerides, insulin and glucose levels before and after oral glucose, and blood pressure were not seen in multivariate analyses. In summary, higher fibrinogen levels were shown to be significantly and independently related to several major lifestyle and physical characteristics known to be associated with increased risk of cardiovascular disease in women.