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OBJECTIVE: Body weight influences the blood metabolome, but whether specific plasma metabolomic profiles predict long-term weight change remains unclear. We aimed to investigate associations among plasma metabolites, current weight, weight change trajectories, and incident type 2 diabetes (T2D) in adults.RESEARCH DESIGN AND METHODS: We profiled 260 plasma metabolites in 7,499 U.S. health professionals. A metabolomic score predicting BMI change over time was derived using elastic net regression with a training/testing approach. Associations with incident T2D were examined using multivariable Cox models.RESULTS: Metabolomic predictors of BMI change varied by baseline weight status. In lean individuals, 46 metabolites significantly predicted BMI change slope compared with 20 individuals in the group with overweight and 13 in the group with obesity, with no overlapping metabolites across groups. A metabolomic score of BMI slope derived in lean participants correlated with BMI slope in the lean group (Spearman r = 0.31), but the correlation was weaker in the groups with overweight (r = 0.16) and obesity (r = 0.10). The score was associated with higher T2D risk in the lean group (hazard ratio [HR] per 1 SD 1.42; 95% CI 1.26-1.60) and group with overweight (HR 1.29; 95% CI 1.17-1.42) but not in the group with obesity.CONCLUSIONS: Plasma metabolomic profiles predictive of future weight change differ by body weight status. Distinct metabolic signatures may help identify certain lean individuals at an elevated risk of future weight gain and T2D, offering opportunities for earlier, more targeted prevention.