The effects of essential fatty acid (EFA) deficiency on connective tissue metabolism were studied in rats deficient in EFA and prostaglandins (PG). In chronic EFA deficiency, 3H-proline fixation, a measure of protein synthesis, was markedly reduced in the stomach, liver, adrenal, kidney, spleen, heart, and small intestine. Collagen rich tissues, such as lung, aorta, and cartilage also demonstrated reduced 3H-proline incorporation. 35S uptake, a measure of glycosaminoglycan synthesis, was inhibited in the lung, kidney, spleen, aorta, small intestine, and cartilage. Shorter periods of EFA deficiency resulted in similar diminished 35S incorporation. However, corn oil supplements largely corrected these metabolic defects. PGE1 injections stimulated 35S uptake in the mucus secreting tissues of the stomach and intestine. Comments are presented suggesting that the anti-PG actions of steroids and non-steroidal anti-inflammatory drugs contribute to ulcer formation during drug therapy.