To calculate the effect of changes in carbohydrate and fatty acid intake on serum lipid and lipoprotein levels, we reviewed 27 controlled trials published between 1970 and 1991 that met specific inclusion criteria. These studies yielded 65 data points, which were analyzed by multiple regression analysis using isocaloric exchanges of saturated (sat), monounsaturated (mono), and polyunsaturated (poly) fatty acids versus carbohydrates (carb) as the independent variables. For high density lipoprotein (HDL) we found the following equation: DELTA-HDL cholesterol (mmol/l)=0.012x(carb-->sat) + 0.009x(carb-->mono) + 0.007x(carb-->poly) or, in milligrams per deciliter, 0.47x(carb-->sat) + 0.34x(carb-->mono) + 0.28x(carb-->poly). Expressions in parentheses denote the percentage of daily energy intake from carbohydrates that is replaced by saturated, cis-monounsaturated, or polyunsaturated fatty acids. All fatty acids elevated HDL cholesterol when substituted for carbohydrates, but the effect diminished with increasing unsaturation of the fatty acids. For low density lipoprotein (LDL) the equation was DELTA-LDL cholesterol (mmol/l)=0.033x(carb-->sat) - 0.006x(carb->-mono) - 0.014x(carb-->poly) or, in milligrams per deciliter, 1.28x(carb-->sat) - 0.24x(carb-->mono) - 0.55x(carb-->poly). The coefficient for polyunsaturates was significantly different from zero, but that for monounsaturates was not. For triglycerides the equation was DELTA-triglycerides (mmol/1) = -0.025x(carb-->sat) - 0.022x(carb-->mono) -0.028x(carb-->poly) or, in milligrams per deciliter, -2.22x(carb-->sat) - 1.99x(carb-->mono) -2.47x(carb-->poly). Thus, replacement of carbohydrates by fat lowered serum triglycerides independent of the nature of the fat. Replacement of saturated by unsaturated fatty acids raised the HDL to LDL cholesterol ratio, whereas replacement by carbohydrates had no effect. Thus, under isocaloric, metabolic-ward conditions the most favorable lipoprotein risk profile for coronary heart disease was achieved if saturated fatty acids were replaced by unsaturated fatty acids, with no decrease in total fat intake. Extrapolation of our data to free-living populations requires more insight into effects of diet on body weight; if high-oil diets promote obesity, then their favorable effects on serum lipids will be lost.