Can the coupling effect among different amino acid components be used to improve the prediction of protein structural classes? The answer is yes according to the study by Chou and Zhang (Crit. Rev. Biochem. Mol. Biol. 30:275-349, 1995), but a completely opposite conclusion was drawn by Eisenhaber et al. when using a different dataset constructed by themselves (Proteins 25:169-179, 1996). To resolve such a perplexing problem, predictions were performed by various approaches for the datasets from an objective database, the SCOP database (Murzin, Brenner, Hubbard, and Chothia. J. Mol. Biol. 247:536-540, 1995). According to SCOP, the classification of structural classes for protein domains is based on the evolutionary relationship and on the principles that govern the 3D structure of proteins, and hence is more natural and reliable. The results from both resubstitution tests and jackknife tests indicate that the overall rates of correct prediction by the algorithm incorporated with the coupling effect among different amino acid components are significantly higher than those by the algorithms without using such an effect. It is elucidated through an analysis that the main reasons for Eisenhaber et al. to have reached an opposite conclusion are the result of (1) misusing the component-coupled algorithm, and (2) using a conceptually incorrect rule to classify protein structural classes. The formulation and analysis presented in this article are conducive to clarify these problems, helping correctly to apply the prediction algorithm and interpret the results.