- A drug composition consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non‐nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) is commonly used in AIDS therapy. A major difficulty encountered with the therapeutic composite involves the emergence of drug‐resistant viruses, especially to the PIs, regarded as the most effective drugs in the composition. We present a novel bioelectronic means to detect the appearance of mutated HIV‐1 exhibiting drug resistance to the PI saquinavir. The method is based on the translation of viral RNA, the association of cleaved or uncleaved Gag polyproteins at an electrode surface functionalized with the respective antibodies, and the bioelectronic detection of the Gag polyproteins associated with the surface. The bioelectronic process includes the association of anti‐MA or anti‐CA antibodies, the secondary binding of an antibody–horseradish peroxidase (HRP) conjugate, and the biocatalyzed precipitation of an insoluble product on the electronic transducers. Faradaic impedance measurements and quartz crystal microbalance analyses are employed to follow the autoprocessing of the Gag polyproteins. The method was applied to determine drug resistance in infected cultured cells and also in blood samples of consenting AIDS patients. The method described here is also applicable to the determination of drug effectiveness in AIDS patients and to screening of the efficiency of newly developed drugs.