Apolipoprotein R (apoR) is a 23-kDa protein found on very low-density lipoprotein (VLDL), on chylomicrons, and in the d > 1.21 g/mL fraction of pig plasma. The plasma concentration of apoR is 5.1 mug/mL, with 11.5% of apoR found on VLDL. In vitro, apoR can transfer from the d > 1.21 g/mL infranatant onto artificial lipid emulsions or human chylomicrons but not onto human VLDL. An apoR cDNA was isolated from a pig liver lambdagt11 expression library. DNA sequence analysis of the apoR cDNA revealed 67% identity with the 3'-terminal region of human C4b-binding protein alpha-chain cDNA (C4BPalpha). C4BPalpha is a 70-kDa glycoprotein that regulates both the coagulation and the complement cascades. In plasma, C4BPalpha exists as disulfide-linked multimers consisting of seven C4BPalpha chains and a single C4BPbeta chain. Like C4BP, apoR forms high molecular weight disulfide-linked complexes in plasma. However, unlike C4BPalpha, apoR complexes do not appear to contain C4BPbeta. ApoR mRNA was detected in pig liver, spleen, lung, bone marrow, and lymph node, but was absent in intestine and white blood cells. This distribution is consistent with the production of apoR in terminally differentiated macrophages but not in blood monocytes. ApoR mRNA was not detected in RNA isolated from human liver or lung. ApoR may be a lipoprotein-borne regulator of either the coagulation or the complement cascades.