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Apolipoprotein M (apoM), a novel human apolipoprotein recently discovered, predominantly presents in high density lipoprotein (HDL) in plasma, exclusively expressed in liver and in kidney. The present data demonstrated apoM protects against atherosclerosis (AS) primarily via partaking in prebeta-HDL formation and promoting cholesterol efflux to HDL. However, this lipid-metabolism-associated pathway seems unlikely responsible for all atheroprotective effects of apoM. Notably, the human apoM gene is just located in the major histocompatibility complex class III region (MHC-III) on chromosome 6, many genes in this region are related to the immune and inflammatory response. Furthermore, apoM has been documented to link with some inflammatory factors including platelet activating factor (PAF) and leptin. These evidences indicate that apoM may be involved in inflammatory activities in vivo and the potential immuno- and inflam-reactive property of apoM may contribute to the anti-inflammatory function of HDL, as generally acknowledged as an important atheroprotective mechanism of HDL.