Studies have suggested that high parity is related to an increased risk of cardiovascular disease (CVD). Reasons for an increased risk are unclear but may include influences of child-bearing on levels of CVD risk factors. The present study examined the associations of parity and CVD risk factors in American Indian women, among whom large families are common. Estrogen use and CVD risk factors also were assessed. The study included 1982 ever-married, postmenopausal women aged 45 through 74 years who participated in the Strong Heart Study (SHS), a large study of American Indians in three geographic areas of the United States. Information was obtained during a physical examination and interview. Parity ranged from 0 to 18 (median 5). Current estrogen use varied from 5% in Arizona to 21% in Oklahoma. Multivariable analyses found a statistically significant, inverse association between parity and high-density lipoprotein (HDL) cholesterol, although the difference with increasing parity was small (-0.26 mg/dl per additional live birth). Estrogen users had significantly lower levels of low-density lipoprotein cholesterol (-6.4 mg/dl) and fibrinogen (-26.2 mg/dl) and a lower waist/hip ratio (-0.02), and higher values of HDL (5 mg/dl) and logarithm (ln) triglyceride (0.13 mg/dl). Current users were slightly more likely to be hypertensive (prevalence odds ratio, 1.56). Relations between parity and CVD risk factors in American Indian women with high parity suggested only small differences with increasing parity. Associations with estrogen use are much stronger and are similar to those observed in other groups of women.