A 2-4-6 subsite-coupled model is proposed to predict the cleavability of peptide sequences by HIV protease. For an enzyme with eight extended specificity subsites, such as HIV protease, the coupling effects of the second subsite with the fourth one and the fourth with the sixth subsite are much more important than those of the others. Accordingly, in establishing a model for predicting whether a given peptide can be cleaved by HIV protease, the 2-4-6 subsite-coupled effect must be incorporated. The model leads to an algorithm for predicting protease-susceptible sites from primary structure. The high rate of correct prediction for both HIV-1 and HIV-2 proteases has borne out that this kind of alternation-coupled mechanism does exist along the extended subsites of HIV protease. The principle of the new method can be used for analyzing the specificity of any multisubsite enzyme. In particular, the new method can serve as a supplementary means for finding effective inhibitors of HIV protease, which is one of the targets in designing potential drugs for AIDS therapy.