A plasmid directing the expression of preapolipoprotein C-III fused to beta-galactosidase was constructed. Escherichia coli harboring this construct produced the hybrid, with full beta-galactosidase activity, at 0.6% of total cellular protein. Purified preapoC-III-beta-galactosidase hybrid exhibited specific binding to very low density lipoproteins, which was inhibited by purified apoC-III. No binding to low density lipoproteins was observed. Binding was mediated by the phospholipids of very low density lipoproteins, as the hybrid had a specific affinity for phospholipids and no detectable affinity for triglycerides, cholesteryl esters, or cholesterol. The differential binding suggests that there are differences between the phospholipids of very low density lipoproteins and the phospholipids of low density lipoproteins.