Sugar is increasingly being blamed for many of our cardiometabolic ills. Lustig et al. argue that sugar is ‘‘toxic’’and as such should be regulated like alcohol or tobacco [1]. Their arguments focus squarely on the ‘‘deadly effect’’of the fructose moiety of sugar. They use a range of observational and mechanistic studies and do not take into account fruit as a significant source of fructose to support their arguments. Does the highest-level evidence that is used to inform clinical practice guidelines and public policy come to the same conclusions? Using systematic reviews and meta-analyses of controlled feeding trials, we came to different conclusions. To address the uncertainties in the evidence, we conducted a series of systematic reviews and meta-analyses of controlled feeding trials of the effect of fructose on cardiometabolic risk (ClinicalTrials. gov registration number: NCT01363791), funded by the Canadian Institutes of Health Research. We found that fructose in isocaloric substitution for other sources of carbohydrate (isocaloric trials) does not increase body weight [2], lipids [3], blood pressure [4], uric acid [5], or insulin [6] and even improves glycemic control [6] in primary analyses (Fig. 1A). There is, however, a signal for harm under certain conditions. High doses of fructose (. 60 g/d in type 2 diabetes [3] and. 100 g/d across different subject types [7]) increase triglycerides in isocaloric trials. Fructose providing excess energy (+ 18%–97%) at extreme doses (+ 104–250 g/d) relative to control diets (hypercaloric trials) also increases body weight, triglycerides, and uric acid (Fig. 1B). The generalizability of these conditions, however, is the issue. The level of fructose exposure exceeds the 95th percentile for US intake (87 g/d)[8] in most of the isocaloric trials and all of the hypercaloric trials, where the median dose is. twofold higher than the 95th percentile for intake [8]. Confounding from excess energy also cannot be excluded in the hypercaloric trials. Formal tests of the effect of the interaction of energy and fructose indicate that the effect of fructose on body weight may not be different from that of other sources of carbohydrate when comparing diets providing equal amounts of energy across the range from negative to positive energy balance [2]. High levels of exposure and excess energy appear to be the dominant considerations for harm. At a time when healthy eating guidelines are encouraging greater fruit consumption [9], what is the role of fruit in this argument?‘‘Fruit and fruit products’’are the largest source of naturally occurring fructose (72.5%) and the third largest source of fructose overall (13.4%) in the US diet [6]. In a randomized controlled feeding trial, Madero et al.[10] showed that naturally occurring fructose from fruit at a dose. 50th percentile for US intake [6](; 60 g/d) decreased body weight, without adverse effects on lipids, blood pressure, uric acid, or insulin resistance, compared with a low-fructose control diet under matched hypocaloric feeding conditions in overweight humans. Improvements in glycemic control seen in a randomized controlled trial investigating the effect of a 6-month low–glycemic index (GI) diet compared with a highcereal fiber diet were also attributable to low-GI fruit as a