During inflammation, serum amyloid A (SAA) protein increases up to 1000-fold and can become a major component of high-density lipoprotein (HDL). We have identified a new apolipoprotein molecule (SAA5) as a distinct member of the SAA family. It differs from the inflammatory isotypes (SAA1, SAA2, and SAA3) not only in structure but in the fact that it is constitutive on normal HDL where it accounts for more than 90% of total SAA. Whereas all members of the SAA family, including SAA5, responded to endotoxin administration, SAA5 contrasted with other SAAs in its resistance to induction either by a high-fat, high-cholesterol atherogenic diet or the injection of mildly oxidized LDL (MM-LDL). These data provide further evidence that the induction of inflammatory molecules by oxidized lipids is selective. In atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant C3H/HeJ mice, the inflammatory SAA isotypes (SAA1, SAA2, and SAA3) responded in a strain-specific manner to oxidized lipids either generated with feeding of the atherogenic diet or introduced by MM-LDL injection. We hypothesize that the constitutive SAA5 molecules on normal HDL may contribute to its normal physiological role and that the dramatic induction of the inflammatory SAA subfamily equips the particle for an altered yet related functional role appropriate to the inflammatory state.