In 23 morbidly obese patients we investigated the influence of a large weight loss (30.6 kg, range 17.5-90.8) on the plasma fibronectin concentrations. Further, changes in plasma fibronectin were related to serum insulin levels and to liver biochemistry. Between the measurements patients had been treated with an intermittent very-low-calorie formula diet sufficient in respect to protein, minerals and vitamins. They were investigated in weight-stable states. Before weight reduction, 14 patients (61%, 95% confidence limits 39-80%) had elevated plasma fibronectin levels. Plasma fibronectin decreased (medians 1.22 and 0.59 mumol/l before and after weight loss, p less than 0.01) and was after weight loss within the normal range in 14 patients. The change in plasma fibronectin was unassociated with the magnitude of the weight loss as well as with the reduction of overweight. The resulting plasma fibronectin levels were also uncorrelated with the body weight and with the final degree of overweight. Serum insulin decreased (p less than 0.01) during the weight reduction and the change correlated (p less than 0.05) with the change in plasma fibronectin. Serum lactate dehydrogenase, which is associated with the degree of hepatic fatty change, declined (p less than 0.01), but the individual change was unrelated with the change in plasma fibronectin. In conclusion, the elevated plasma fibronectin levels in morbidly obese subjects seem to normalize during weight loss. We suggest the normalization to be mediated--at least in part--by a reduction of the insulin levels.