The main therapeutic targets in HIV are its protease and reverse transcriptase. A major problem in treatment of HIV is the ability of the virus to develop drug resistance by accumulating mutations in its targets. Acquiring detailed understanding of the molecular mechanisms for the interactions of drugs with mutated variants of the HIV virus is mandatory to be able to design inhibitors that can evade the resistance. Here we have used proteochemometric modeling to simultaneously analyze the interactions of 21 protease inhibitors with 72 unique protease variants. Inhibition data (pK(i)) were correlated to descriptions of chemical and structural properties of the inhibitors and proteases. The proteochemometric model obtained showed excellent fit and predictive ability (R(2)=0.92, Q(2)=0.83, Q(2)(inh)=0.78) and provided quantitative assessments for the contribution of each mutation and their combinations to the decrease in inhibitor activity, both for the whole compounds series as well as for individual compounds. The model revealed the most deleterious mutations in the protease to be D30N, V32I, G48V, I50V, I54V, V82A, I84V, and L90M. The model was further used to identify molecular properties of chemical compounds that are important for their inhibition of multimutated protease variants. Our results give directions how to design novel improved inhibitors.