The behavior of human apolipoprotein C-II (apoC-II; molecular weight, 8,837) has been studied in an aqueous solution by using gel permeation chromatography, sedimentation equilibrium ultracentrifugation, and circular dichroic (CD) spectroscopy. The elution volume of apoC-II was equivalent to that of standard proteins with molecular weights of 30,000 and 17,800 by high performance liquid chromatography (HPLC) on TSK-Gel G3000SW and by gel permeation chromatography on Sephadex G-75, respectively. Sedimentation equilibrium experiments in a table-top high-speed air turbine centrifuge and in an analytical ultracentrifuge showed values of 9,400 and 7,900, respectively, for the molecular weight of apoC-II in the absence of any denaturants or surfactants. The CD spectrum of apoC-II in the far-ultraviolet region indicated that it had a highly disordered structure. These results showed that the apoC-II molecule, when in dilute solution, is dominantly monomeric with an extended and loosely folded structure. The concentration dependence of the ellipticities at 220 nm and of the molecular weight in the sedimentation equilibrium experiment suggests that apoC-II self-associates weakly in an aqueous solution. The disordered state of apoC-II was highly stable. However, helical conformation was induced by sodium dodecylsulfate, trifluoroethanol, and phosphatidylcholine vesicles.