We have examined the secondary structures of human class I and class II histocompatibility antigens in solution by Fourier transform infrared spectroscopy and circular dichroism in order to compare the relative amounts of alpha-helix, beta-sheet, and other structures, which are crucial elements in the comparison of the protein structures. Quantitation of infrared spectra of papain-solubilized HLA-A2, HLA-B7, and DR1 in phosphate buffer gave alpha-helix contents of 17%, 8%, and 10% and beta-sheet contents of 41%, 48%, and 53%, respectively. By circular dichroism, papain-solubilized HLA-A2, HLA-B7, and DR1 were also found to have comparable alpha-helix contents (e.g., 8%, 20%, and 17%, respectively). Circular dichroism analysis for beta-sheet gave 29% for papain-solubilized HLA-B7 and 42% for papain-solubilized DR1. The value for papain-solubilized HLA-A2 (74%) was anomalous. It is proposed that Trp-107 of HLA-A2, missing in both HLA-B7 and DR1, may be responsible for much of the anomaly. Due to the uncertainties inherent in quantitation of the amounts of secondary structures by both spectral methods, the differences in the contents of alpha-helix and beta-sheet in the three proteins are not considered significant. However, differences in the nature of the beta-sheet structures are suggested by infrared spectroscopy. These results provide physical evidence for an overall structure of class II antigens modeled on that of class I antigens.