Background <p>Bariatric surgery (BS) improves long-term glycemic control more effectively than medical treatment in patients with type 2 diabetes mellitus. The objective of this study was to explore the dynamic changes on inflammatory and metabolic-related circulating proteins in a large cohort of overweight patients and patients with class I to III obesity undergoing bariatric surgery (BS).</p> Subjects/methods <p>We performed quantitative proteomic analysis (399 inflammatory/metabolic proteins, Olink Proteomics) in plasma samples collected before (<i>n</i> = 114) and 1 month (<i>n</i> = 67), 3 months (<i>n</i> = 64), 6 months (<i>n</i> = 60), 12 months (<i>n</i> = 48) and 24 months (<i>n</i> = 18) after either Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG).</p> Results <p>Circulating proteins primarily expressed in the liver markedly changed after BS including IGFBP-1/2 (upregulated at all time points post-surgery) and the peroxisomal enzyme HAOX1 (downregulated at all time points post-surgery). Regression analysis revealed a strong association between the changes in HAOX1 and improvements in liver enzymes. In addition, a soluble broad-spectrum pattern recognition receptor, scavenger receptor cysteine rich family member with 4 domains (SSC4D), exhibited the highest decrease among all proteins at 24 months post-surgery. Finally, we detected that inflammatory markers were transiently increased after RYGB compared to VSG as well as in patients with severe obesity compared to patients with overweight and patients with obesity at 1-month post-surgery.</p> Conclusions <p>This study identified novel inflammatory and metabolic proteins possibly implicated in the systemic metabolic response to BS.</p>