The possible role of C-reactive protein (CRP) in the etiology and prognosis of ischemic stroke remains to be clearly defined. The purpose of this study was to determine whether CRP levels are elevated in patients with stroke, whether they remain persistently elevated, and whether CRP levels are higher in patients with etiologic subtypes of stroke caused by large or small artery disease (“atherogenic hypothesis”) or whether they may be higher in patients with more extensive cerebral infarction caused by large artery or cardiogenic embolism (“inflammatory hypothesis”). We conducted a case-control study of 199 hospital cases with a first-ever ischemic stroke and 202 randomly selected community controls. Cases of stroke were classified by etiologic subtype and the prevalence of conventional vascular risk factors and CRP levels were determined in cases and controls. Blood levels of CRP measured within 7 days of acute stroke were significantly higher in cases compared with controls (8.50 vs. 2.18 mg/L, P <.0001) and remained elevated in stroke survivors at 3 to 6 months of follow-up (3.35 vs. 2.18 mg/L, P = .003) although levels were significantly lower compared with the first 7 days (3.35 vs. 8.50 mg/L, P <.001-.003). Compared with the lowest quartile of CRP, the upper 3 quartiles were associated with an adjusted odds ratio (OR) of ischemic stroke of 1.9 (95% CI: 1.0-3.8) for the second quartile, 5.8 (95% CI: 2.9-11.4) for the third quartile, and 16.9 (95% CI: 7.9-36.1) for the fourth quartile (P for trend <.0001). Comparing the upper with the lower quartile, the strongest association was with etiologic stroke subtypes caused by large artery disease (OR 52.5; 95% CI: 13.4-205) and embolism from the heart (OR 56.1; 95% CI: 11.3-278), with a much weaker association with small artery disease (OR 2.4; 95% CI: 0.8-6.0). The mean Oxford Handicap Scale score was lowest in small artery, intermediate in large artery and highest in cardioembolic stroke (2.8 vs. 3.1 vs. 3.6, respectively; P = .001) while the mean Barthel Index was highest in small artery, intermediate in large artery, and lowest in cardioembolic stroke (13.5 vs. 11.5 vs. 8.6, respectively; P = .002). Furthermore, there was a significant correlation between CRP levels during the first 7 days and stroke severity, as measured by the Oxford Handicap Scale score (P = .03) and Barthel index (P = .001). We conclude that there is a strong, independent relationship between elevated blood levels of CRP and ischemic stroke, particularly because of more severe strokes caused by large artery disease and embolism from the heart, which remains evident over the long term. These results are consistent with the inflammatory marker hypothesis of CRP as a marker of the extent of ischemic cerebral injury and its complications.