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BACKGROUND: Clinical trials have shown that interleukin-6 (IL-6) signaling inhibitors reduce lipoprotein(a) [Lp(a)] levels, though the relevance of this reduction to atherosclerotic cardiovascular disease (ASCVD) risk is uncertain. We leveraged Mendelian randomization (MR) to investigate the extent to which Lp(a) reduction mediates the effects of IL-6 signaling inhibition on ASCVD.METHODS: IL-6 signaling inhibition was proxied by the IL6R variant p.Asp358Ala and scaled to C-reactive protein (CRP) levels. Genetic associations with Lp(a) were obtained from UK Biobank (n = 343,681). Outcomes included large-artery atherosclerotic stroke (LAAS: 6399 cases), carotid plaque (29,760 cases), and coronary artery disease (CAD: 181,522 cases). MR analyses estimated the association of IL-6 signaling inhibition with Lp(a) and ASCVD, and we quantified the proportion of the IL-6-ASCVD association mediated by Lp(a). Individual-level analyses tested whether effects of IL-6 signaling inhibition on Lp(a) and CAD were amplified in carriers of Lp(a)-raising variants.RESULTS: Genetically proxied IL-6 signaling inhibition modestly reduced Lp(a) (-3.01 mg/dL per 1-ln(CRP) reduction, 95% CI -4.79, -1.23) and protected against all ASCVD outcomes (ORs: 0.34-0.69). Lp(a) mediated only a small proportion of the IL-6-ASCVD association (range: 1.3%-4.8%). In carriers of Lp(a)-raising variants, the IL-6-Lp(a) association was stronger (-9.8 mg/dL, 95% CI -14.6, -5.1; p = 6.38 Ã— 10), though IL-6-CAD associations were similar (p = 0.75) and the proportion mediation remained low (4.2%-15.6%).CONCLUSIONS: These findings suggest that Lp(a) minimally mediates and does not modify the cardiovascular benefits of IL-6 signaling inhibition, supporting these targets as independent and complementary for ASCVD. The amplified IL-6-Lp(a) association in carriers of Lp(a)-raising variants warrants replication.