The amino acid sequence of chicken apolipoprotein CII (apoCII) was determined from cDNA sequencing and from partial protein sequencing. The chicken sequence showed an overall identity of around 30% to all the other previously known apoCII sequences. Comparison of the carboxyl-terminal domain (residues 51-79, human numbering) showed at least 50% identity between species. By limiting the region to residues 51-70 the similarity was remarkably high, about 85%. This is in concert with the previous opinion that residues in the region 56-76 are directly engaged in binding to lipoprotein lipase and in activation of this enzyme. In contrast, in the amino-terminal end up to residue 50 (human numbering) less than 24% of the amino acid residues in chicken apoCII were identical to residues of any of the other species. In addition, chicken apoCII is four residues longer than human apoCII (83 versus 79 residues), probably due to an extension at the amino-terminal end. Although the sequence was completely different in the amino-terminal domain, the structures necessary for binding to lipid appear to be present in chicken apoCII. Secondary structure prediction showed that the amino-terminal domain could form two amphipathic alpha-helices in almost similar areas of the sequence as was previously predicted for human apoCII.