BACKGROUND AND PURPOSE The mechanisms underlying neurological deterioration in patients with lacunar infarction are not completely understood. In this study, we sought to investigate the role of proinflammatory molecules in the early worsening and outcome of acute lacunar stroke. METHODS We performed a secondary analysis of 113 consecutive patients with lacunar infarction included within the first 24 hours of the onset of symptoms in a previous study aimed at investigating clinical and biochemical factors of early neurological deterioration (END). END was defined as a fall of > or =1 points in the motor items of Canadian Stroke Scale between inclusion and 48 hours. Poor outcome at 3 months was considered death or Barthel Index <85. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1) were determined by enzyme-linked immunoabsorbent assay in blood samples obtained on admission. RESULTS END was recorded in 27 patients (23.9%); poor outcome was noted in 26 (23%). Median (quartiles) concentrations in plasma of TNF-alpha [16.5 pg/mL (13.7 and 21.2 pg/mL) versus 7.5 pg/mL (6.2 and 9.0 pg/mL)], IL-6 [28.8 pg/mL (22.5 and 35.7 pg/mL) versus 11.5 pg/mL (8.5 and 16.2 pg/mL)], and ICAM-1 [285 pg/mL (219 and 315 pg/mL) versus 158 pg/mL (137 and 187 pg/mL)] were significantly higher in patients who had END than in those with nonprogressing strokes (P< 0.001). Significant differences were also observed between patients with poor and good outcome at 3 months. Logistic regression analysis after adjustment for potential confounders showed that TNF-alpha >14 pg/mL and ICAM-1 >208 pg/mL were independently associated with both END (OR, 511; 95% CI, 17 to 4937; P<0.001; and OR, 315; 95% CI, 17 to 5748; P< 0.001, respectively) and poor outcome at 3 months (OR, 3.0; 95% CI, 1.0 to 8.5; P=0.042; and OR, 4.2; 95% CI, 1.3 to 13.6; P<0.015, respectively). CONCLUSIONS High concentrations of inflammatory markers in blood are associated with END and poor functional outcome in lacunar infarctions. These findings suggest that inflammation contributes to brain injury in lacunar stroke.