High density lipoprotein (HDL) levels decrease during the acute phase response (APR). We have used the APR model of rabbit, baboon, and mouse to study the factors that influence HDL level. In the baboons and rabbits there was massive hypertriglyceridemia, triglyceride enrichment of HDL (60-80% of core lipids), decreases of HDL-cholesterol and apolipoprotein (apo)A-I (to 10% of baseline), and increases of apoA-I in the non-lipoprotein bottom fraction suggesting dissociation of apoA-I from the particles. Detailed analyses of serum amyloid A (SAA)-rich HDL done in the rabbit revealed large, triglyceride-enriched (> 60% of core lipids) particles containing > 95% SAA. These particles had a high surface to core ratio (13.4 +/- 1.94, control = 3.0 +/- 0.12) and a very high protein (79.71 +/- 5.25 weight %, control = 37.2 +/- 0.43) proportion, large (r = 5.95 nm) when examined by non-denaturing gradient electrophoresis but small when examined by electron microscopy (r = 4.2 nm). In the mouse there was no hypertriglyceridemia, no triglyceride enrichment of HDL, no decrease of HDL cholesterol. ApoA-I decreased to about 61.4% of baseline but did not increase in the bottom fraction although large but dense SAA-enriched HDL particles were also produced. These results suggest that hypertriglyceridemia, triglyceride-enrichment of HDL, and dissociation of apoA-I from the particles, possibly by displacement of apoA-I by SAA, are important factors in the decline of HDL during the APR. Whether differences in triglyceride metabolism account for the differences in the HDL response in the species studied requires further experimentation.