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Fetuin-A (Fet-A), secreted by the liver into circulation, inhibits insulin-stimulated insulin receptor tyrosine kinase and is positively associated with obesity, insulin resistance, and incident diabetes. Though Fet-A exists in both phosphorylated and dephosphorylated forms in circulation, there are limited studies on its phosphorylation status or molecular characterization. The goal of this study was to investigate the role of phosphorylation of Fet-A in insulin action, insulin resistance, obesity and weight loss. We hypothesized that Ser312 phosphorylation status of Fet-A (pFet-A) is (a) critical for inhibition of insulin signaling and (b) associated with obesity and insulin resistance. While wild-type phosphorylated Fet-A blunted insulin signaling (IR, AKT, and MAPK, GLUT4 translocation), glucose uptake, and glycogen synthesis, single (Ser312Ala) and double (Ser312Ala+Ser120Ala) phospho-defective Fet-A mutants were without effect. To investigate the role of phosphorylation of Fet-A in insulin resistance, obesity and weight loss, we recruited 31 age-matched obese and 11 normal weight men. Circulating Fet-A and pFet-A were significantly elevated in obese individuals. Only pFet-A was significantly associated with serum glucose, insulin, HOMA, QUICKI and glucose-to-insulin ratio (G:I ratio). Following (24 hours after) a single bout of exercise, the area under the curve (AUC) for glucose, insulin, Fet-A and pFet-A were significantly lower. Next, 16 obese subjects took part in a modest weight loss study (8 - 10% of initial body weight) over a 6 to 10 month time period. Weight loss significantly decreased waist circumference, percent body fat, serum insulin, HOMA, QUICKI, and G:I ratio. While Fet-A and pFet-A levels were significantly lower, only pFet-A levels were correlated with insulin, HOMA, QUICKI, and G:I ratio. Taken together, we demonstrate for the first time that phosphorylation status of Fet-A (Ser312) is critical for its inhibitory effects on insulin action. Elevated serum pFet-A concentrations observed in obese individuals correlate positively with surrogate markers of insulin resistance. Alterations in pFet-A following a single bout of exercise or with modest weight loss are associated with the improvement of insulin sensitivity. Our studies suggest a key role for pFet-A in the modulation of insulin action.