There is abundant evidence that dietary omega 3 fatty acids effect a favorable change in lipoprotein profiles of normolipidemic individuals. However, there is relatively little information available on the lipoprotein responses of hyperlipidemic individuals at risk for premature coronary artery disease. We studied a group of subjects with familial combined hyperlipidemia (FCHL), as well as a group of normal controls, on three rigidly controlled diets differing primarily in their fatty acid composition. The normal subjects demonstrated significant reductions in total cholesterol, low density lipoprotein (LDL) cholesterol, and total apolipoprotein B (apo B) levels on both an omega 3 (salmon) and omega 6 (safflower) fatty acid-enriched diet when these were compared with a basal diet high in saturated fat. The primary difference in response to the polyunsaturated diets was the potent triglyceride-lowering effect of the salmon diet. The FCHL subjects demonstrated a response to the safflower diet similar to that observed in normals and also manifested a marked triglyceride lowering with the salmon diet. However, total cholesterol and total apo B levels were not lowered by the salmon diet, and LDL cholesterol and apo B levels exhibited an upward trend. Thus, individuals with FCHL, a common disorder associated with premature coronary artery disease, do not appear to have a favorable lipoprotein response to diets enriched in omega 3 fatty acids.