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RIPK1 (receptor-interacting serine/threonine-protein kinase 1) enzymatic activity drives both apoptosis and necroptosis, a regulated form of necrosis. Because necroptosis is involved in necrotic core development in atherosclerotic plaques, we investigated the effects of a RIPK1^S25D/S25D mutation, which prevents activation of RIPK1 kinase, on atherogenesis in ApoE^−/− mice. After 16 weeks of western-type diet (WD), atherosclerotic plaques from ApoE^−/− RIPK1^S25D/S25D mice were significantly larger compared to ApoE^−/− RIPK1^+/+ mice (167 ± 34 vs. 78 ± 18 × 10³ µm², <i>p</i> = 0.01). Cell numbers (350 ± 34 vs. 154 ± 33 nuclei) and deposition of glycosaminoglycans (Alcian blue: 31 ± 6 vs. 14 ± 4%, <i>p</i> = 0.023) were increased in plaques from ApoE^−/− RIPK1^S25D/S25D mice while macrophage content (Mac3: 2.3 ± 0.4 vs. 9.8 ± 2.4%, <i>p</i> = 0.012) was decreased. Plaque apoptosis was not different between both groups. In contrast, pharmacological inhibition of RIPK1 kinase with GSK’547 (10 mg/kg BW/day) in ApoE^−/− Fbn1^C1039G+/− mice, a model of advanced atherosclerosis, did not alter plaque size after 20 weeks WD, but induced apoptosis (TUNEL: 136 ± 20 vs. 62 ± 9 cells/mm², <i>p</i> = 0.004). In conclusion, inhibition of RIPK1 kinase activity accelerated plaque progression in ApoE^−/− RIPK1^S25D/S25D mice and induced apoptosis in GSK’547-treated ApoE^−/− Fbn1^C1039G+/− mice. Thus, without directly comparing the genetic and pharmacological studies, it can be concluded that targeting RIPK1 kinase activity does not limit atherogenesis.