The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PRV82Aand PRL90M,have been determined in complex with the antiviral drug, indi-navir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (Ki)of PRV82Aand PRL90Mwas and , respectively, relative to the value for PR. They showed only a modest decrease, of 10–15%, in theirkcat /Kmvalues relative to PR. .