Consumption of industrially produced trans-fatty acids (TFA) is associated with substantial risk of coronary heart disease (CHD). The magnitude of this relationship, as well as emerging associations with end points such as diabetes and sudden cardiac death, cannot be fully explained by the well-established adverse effects of TFA on serum lipids. We review the evidence for effects of TFA intake on nonlipid risk factors. Based on evidence from randomized controlled trials, observational studies, animal experiments, and in vitro studies, these include effects on systemic inflammation, endothelial dysfunction, visceral adiposity, insulin resistance, and arrhythmic risk. The types and strength of evidence for each of these nonlipid effects varies, but the overall constellation of findings is qualitatively and quantitatively unique among dietary fats. The multiple adverse effects and implicated pathways are consistent with the observed strong associations of TFA consumption with CHD risk. These nonlipid effects also explain why TFA consumption may adversely impact other non-CHD diseases and end points.