The fatty acid compositions of serum phospholipids, cholesteryl esters, triglycerides, and free fatty acids were determined on a group of cystic fibrosis patients. These were compared with similar data from random hospitalized patients of the same age groups of both sexes. Fatty acid patterns in all lipid classes were skewed in the direction of essential fatty acid deficiency, but the differences were most dramatic in phospholipids. Many calculated parameters useful as indices of essential fatty acid status indicated that essential fatty acid deficiency exists in cystic fibrosis. Treatment of 11 cystic fibrosis patients with safflower oil (1 g/kg/day) failed to correct the aberrations in fatty acid pattern. The biochemical data suggest that there may be an impairment in conversion of linoleate to arachidonate as well as an impairment of absorption.