To evaluate alterations in fibronectin homeostasis in preeclampsia we measured the plasma concentrations of fibronectin bearing an extra type III domain in 33 preeclamptic and 36 control patients at varying gestational ages. This fibronectin variant is concentrated in the endothelium of blood vessels and has been shown to be released at sites of vascular injury. In addition, total circulating fibronectin levels, composed primarily of hepatic-derived fibronectin lacking the extra type III domain, were also determined. Significant elevations in the average circulating concentrations of fibronectin with an extra type III domain (5.5 micrograms/ml [95% confidence interval, 4.7,6.2] versus 3.2 micrograms/ml [95% confidence interval, 2.9,3.5]; p = 0.0001) as well as total fibronectin (387 micrograms/ml [95% confidence interval, 357,417] versus 327 micrograms/ml [95% confidence interval, 305,348]; p = 0.036) were observed in preeclamptic versus control patients. Significant elevations in fibronectin levels with an extra type III domain occurred in the first trimester before clinical evidence of preeclampsia. In addition, multivariate logistic regression demonstrated a 5.4-fold increase in the risk of preeclampsia with each 1 microgram/ml elevation in concentration of fibronectin with an extra type III domain. These findings lend support to the hypothesis that endothelial-vascular injury is a primary event in the genesis of preeclampsia.