Dietary weight loss regimens could be more effective by selectively targeting adipose while sparing lean mass (LM) if predictive information about individuals' lipid metabolic responses to an intervention were available. The objective of this study was to examine the relationships among changes in 4 anthropometric outcomes, weight, waist circumference (WC), percent body fat (BF), and percent LM, and comprehensive circulating lipid metabolites in response to energy reduction in overweight participants. This was a cohort study (n = 46) from a larger multi-center (n = 105) weight loss trial. We used stepwise regression to examine relationships among baseline plasma fatty acids of 7 lipid classes, biochemical metabolites, and diet to explain the variance of 4 anthropometric outcomes after intervention. No predictor variables explained the variance in the percent change in body weight. The circulating concentration of FFA 18:1(n-9) at baseline explained 31% of the variance in percent change of WC, with adjustment for energy intake at 12 wk. Circulating concentrations of phosphatidylcholine 18:0 and FFA 18:1(n-9) at baseline together explained 33% of the variance in percent LM change. The circulating concentration of phosphatidylcholine 18:0 at baseline explained 23% of the variance in the change in percent BF. This study determined relationships among comprehensive and quantitative measurements of complex lipid metabolites and metabolic outcomes as changes in body composition. Measurements of plasma circulating metabolites explained 20-30% of the variance in changes in body composition after a weight loss intervention. Thus, circulating lipids reflect lipid metabolism in relation to changes in body composition.