To replace dietary trans fatty acids (TFA), two practical options exist: revert to a natural saturated fat without cholesterol (most likely palm oil or its fractions) or move to a newer model of modified fat hardened by interesterification (IE). This review summarizes the relative risks for cardiovascular disease inherent in these options. Interestingly, both types of fat have been the subject of nutritional scrutiny for approximately the last 40 years, and both have positive and negative attributes. Only during that period has palm oil production developed to the point where it has become the major edible oil in world markets, making clinical studies of it an important objective. On the other hand, approximately 25 human studies have fed interesterified fat in one form or another over this period, some for weeks, some as a single meal. Two types of diet designs exist. Several fed a small amount of interesterified fat, usually incorporated within a margarine, and stayed below the radar of biological detection of any abnormal metabolism. A few fed interesterified fat that incorporated stearic acid, as interesterified 18:0 (IE-18:0), even comparing it to trans fat and saturated fat, as a major part of total daily calories to assess its metabolic impact per se. These latter 5 to 6 studies clearly reveal negative biological effects on lipoproteins, blood glucose, insulin, immune function, or liver enzymes when relatively high intake of IE-18:0 or palmitic acid (IE-16:0) were fed in fats with sn2-saturated fatty acids. High intake of 18:0 in natural fats can depress total lipoproteins, while IE-18:0 and IE-16:0 at high levels adversely affect lipoprotein metabolism. Still other studies have supplied interesterified fat as a single meal or fed such fat daily only in a single snack, as opposed to incorporating the fat into the entire fat pool consumed at all meals in association with most foods (which is the more physiological approach and more apt to elicit effects). Even in meal studies, IE-18:0 typically delayed fat absorption postprandially, indicating its effect on fat metabolism originating, in part, in the intestine. Mainly 2 saturated fatty acids (18:0 or 16:0) have been interesterified to harden oils, using the 16:0 from fully hydrogenated palm oil or 18:0 from fully hydrogenated soybean oil as the source material. It is not clear that IE-16:0 is as problematic as IE-18:0, but IE-16:0 has been studied less. Levels between 8% energy (%E) and 12%E from 18:0 as interesterified fat (the typical diet provides about 2%E-4%E as 18:0 from natural fats) show the most effect. Detection of adverse effects would seem to start around 7%E-8%E as IE-18:0, but one can assume that effects are initiated, even if undetected, at a lower intake, similar to the situation with TFA. Thus, although an intake of 1%E to 4%E from IE-18:0 does not appear to influence lipoproteins, it is not necessarily the only system affected. The negative effects of IE-18:0 may be alleviated or masked by dilution with other fats, especially by adding 18:2-rich polyunsaturated oils to the diet. This is similar to the trans fat story, i.e., if a limited intake of TFA is heavily diluted with other oils, the consumption of TFA fails to be detected as an adverse effect. Accordingly, more research is warranted to determine the appropriateness of interesterified fat consumption, particularly before it becomes insidiously embedded in the food supply similar to TFA and intake levels are achieved that compromise long-term health.