The effects of leptin-replacement therapy on the plasma proteome of three unique adults with genetically based leptin deficiency were studied longitudinally during the course of recombinant human leptin-replacement treatment. Quantitative proteomics analysis was performed in plasma samples collected during four stages: before leptin treatment was initiated, after 1.5 and 6 years of leptin-replacement treatment, and after 7 weeks of temporary interruption of leptin-replacement therapy. Of 500 proteins reliably identified and quantitated in those four stages, about 100 were differentially abundant twofold or more in one or more stages. Synchronous dynamics of abundances of about 90 proteins was observed reflecting both short- and long-term effects of leptin-replacement therapy. Pathways and processes enriched with overabundant synchronous proteins were cell adhesion, cytoskeleton remodeling, cell cycle, blood coagulation, glycolysis, and gluconeogenesis. Plausible common regulators of the above synchronous proteins were identified using transcription regulation network analysis. The generated network included two transcription factors (c-Myc and androgen receptor) that are known to activate each other through a double-positive feedback loop, which may represent a potential molecular mechanism for the long-term effects of leptin-replacement therapy. Our findings may help to elucidate the effects of leptin on insulin resistance.