Adiponectin exhibits diverse protective effects against atherogenesis and antagonizes many effects of TNFα. Here, we investigated the effect of adiponectin and TNFα on vascular calcification, a critical event in the development and progression of vascular disease. In human aortic smooth muscle cells (HASMC), TNFα augmented inorganic phosphate (Pi)-induced calcification, whereas adiponectin significantly suppressed it and abolished the stimulatory effect of TNFα in a concentration-dependent manner. Similarly, adiponectin ameliorated the accelerating effect of TNFα on Pi-induced apoptosis, the essential process of HASMC calcification. Furthermore, these effects of TNFα and adiponectin were associated with AMP-activated protein kinase (AMPK)-dependent growth arrest-specific gene 6 (Gas6) expression and Akt signaling. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced phosphorylation of AMPK and significantly inhibited Pi-induced calcification in HASMC. Conversely, pharmacological inhibition of AMPK by compound C blocked both AMPK activation and the inhibitory effect of adiponectin on calcification, providing evidence that AMPK plays a regulatory role in vascular calcification. Reporter assay revealed that adiponectin restored Gas6 promoter activity decreased by TNFα, and the effect of adiponectin was abrogated by compound C. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFα on vascular calcification by restoration of the AMPK-dependent Gas6-mediated survival pathway.