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Background and Purpose Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. Methods Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a Phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment, and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95%CI) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. Results Among 1244 lacunar stroke patients (mean 63.3 ± 10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes), and 115 major vascular events (stroke, myocardial infarction, vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP >4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR 2.54, 95%CI 1.30–4.96), even after adjusting for demographics and risk factors (adjusted HR 2.32, 95%CI 1.15–4.68). HsCRP predicted increased risk of major vascular events (top quartile adjusted HR 2.04, 95%CI 1.14–3.67). There was no interaction with randomized antiplatelet treatment. Conclusions Among recent lacunar stroke patients, hsCRP levels predict risk of recurrent strokes and other vascular events. HsCRP did not predict response to dual antiplatelets.