BACKGROUND: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke. METHODS: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995-2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication. RESULTS: Overall 10 148 patients (3448 [34.0%] had atherosclerosis) with 21 177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08-1.37]; per logeunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08-1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37-3.08]) and stroke (RR, 1.97 [95% CI, 1.28-3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01-1.23]) but not stroke (RR, 1.08 [95% CI, 0.98-1.20]; per logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05-1.21]; per logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01-1.14]; Pinteraction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98-1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91-1.04]; Pinteraction=0.18). CONCLUSIONS: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.