- OBJECTIVE Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain. RESEARCH DESIGN AND METHODS We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss. RESULTS We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0–6) going in the opposite direction to that in the weight maintenance/regain phase (months 7–24) ( P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL-C, high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement ( P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B. CONCLUSIONS hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.