Conformational transitions of human alpha-fetoprotein (AFP) in the pH range from 2 to 12 were studied by fluorescence spectroscopy, fluorescence polarization, and circular dichroism in order to compare the molecular architecture of AFP with that of human serum albumin (HSA). In a previous paper we have found that AFP has a remarkably hydrophilic exposed molecular surface at neutral pH and possesses extensive hydrophobic binding sites located in crevices. Conformational changes of AFP occur in the acid and alkaline pH regions; extensive, hydrophobic areas of AFP are exposed by both acid and alkaline transitions. Similar results were obtained using optical methods. Both fluorescence and CD measurements disclosed conformational transitions of AFP induced by acidic or alkaline pH. Changes of the fluorescence intensity of AFP and HSA were compared with the model substances, that is, with lysozyme and Gly-Trp dipeptide. Again AFP and HSA show similar features, especially at the neutral pH and during alkaline transition. In the acid pH region, decrease of the AFP emission fluorescence intensity was greater than that of HSA and evidence for some irreversible conformational changes of AFP was obtained. CD spectra of both proteins also show a very similar pattern. The changes of molar ellipticity with pH for HSA are very much like those found for AFP. We have estimated high alpha-helix content--67% at pH 7.6 and 47% at pH 2.11. These figures are very close to those given for bovine albumin and rat alpha-fetoprotein. These findings provide additional support for our former findings that the molecular architecture of human alpha-fetoprotein has features similar to those of human serum albumin.