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Visual Abstract, Highlights • Genetic and functional evidence suggests that there are additional inflammasome pathways, besides NLRP3, that contribute to IL-1 generation in human atherosclerotic plaques. • Plaque generation of mature IL-1β is accompanied by secretion of similar levels of IL-1α, through a mechanism controlled by NLRP3 and caspase-1. • Plaque IL-1β production is higher in patients with uncontrolled hyperlipidemia, on no or low-dose statin therapy, or with complex plaque imaging features. • The present study lends support to high-intensity cholesterol lowering and anti-IL-1-directed therapies for patients at high cardiovascular risk., Summary CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) confirmed interleukin (IL)–1β as an appealing therapeutic target for human atherosclerosis and related complications. However, there are serious gaps in our understanding of IL-1 production in atherosclerosis. Herein the authors show that complex plaques, or plaques derived from patients with suboptimally controlled hyperlipidemia, or on no or low-intensity statin therapy, demonstrated higher recruitable IL-1β production. Generation of mature IL-1β was matched by IL-1α release, and both were attenuated by inhibition of NLR family pyrin domain containing 3 or caspase. These findings support the inflammasome as the main pathway for IL-1α/β generation in atherosclerosis and high-intensity lipid-lowering therapies as primary and additional anti-IL-1-directed therapies as secondary interventions in high-risk patients.