At present, no information is available about the possibility that acute loss of metabolic control might be able to modify fatty acid composition in IDDM patients. Therefore, the aim of this study was to determine whether a short-term period of ketosis has any effect on the composition of fatty acid of plasma phospholipids in a group of insulin-dependent diabetes mellitus (IDDM) patients. Eleven IDDM patients and nine healthy volunteers were studied. Patients were studied over a 2-day period; each 2-day period consisted of initial baseline measurements followed by a day of hyperglycemia and mild ketosis, which was promptly alleviated by insulin infusion. No significant difference in baseline percent fatty acid composition was observed between normal controls and IDDM patients. In IDDM patients, ketosis induced a significant decrease in percent arachidonic acid (20:4 n-6) content, with a significant parallel decline in n-6 total polyunsaturated fatty acids. A significant inverse correlation between the prevailing plasma glucose and the relative content of arachidonic acid in plasma phospholipids was observed (r = -0.35; P = 0.0488). A highly significant inverse correlation was observed between the change from baseline condition to ketosis of the ratio C20:4/C20:3, the product/precursor ratio for the reaction catalyzed by delta5-desaturase, and the values of hemoglobin A1c,(r = -0.855; P = 0.0015). In conclusion, short term diabetic ketosis is associated with a significant decrease in n-6 polyunsaturated fatty acid content in plasma phospholipids, especially arachidonic acid. This decrease in arachidonic acid appears to be related to the degree of metabolic derangement, whereas the influence of short-term diabetic ketosis on the ratio of C20:4 to C20:3 seems to be due to the degree of long-term metabolic control.