Abstract Human immunodeficiency virus type 1 (HIV-1) has high mutation rates and exists as mutant swarms within the host. The adaptive immune system recognizes cognate epitopes based on amino acid sequences and associated conformations that are subject to mutation. The within-host diversity of HIV-1 allows rapid selection of antibody and T cell escape variants, leading to viral persistence. Approaches to target immutable components are needed to clear HIV-1 infection. Here, we report that the CARD8 inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells prior to viral budding. Induction of premature intracellular activation of the viral protease triggers CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. The viral protease activity against CARD8 is well conserved across major HIV-1 subtypes. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Taken together, our study identifies CARD8 as an inflammasome sensor of HIV-1 that holds promise as a strategy for clearance of persistent HIV-1 infection.