To evaluate impact of glucose burden on diffusion-weighted imaging (DWI)-lesion evolution according to ischemia duration in stroke. We studied 47 patients with transcranial Doppler (TCD)-documented artery occlusion treated with intravenous tissue plasminogen activator. Hyperglycemia (HG) was defined as glucose>140 mg/dL. A subcutaneous device continuously monitored glucose during 24 h. Magnetic resonance imaging was performed pretreatment (1) and at 24 to 36 h (2) in 30 patients. We measured initial PWI lesion (PW1) and DWI growth: DW2-DW1 (DWg). Serial TCD during 24 h determined occlusion time (OT). National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 h. Poor short-term clinical course defined as <50% recovery of initial NIHSS. Baseline NIHSS was 18. On admission 10 patients (21.3%) were hyperglycemic and presented similar NIHSS, DW1, and PW1 lesion extension as those without HG. During monitoring 24 patients (51%) had HG, 21 (45%) of them during OT (median OT 12 h). Median 48 h-NIHSS was 10; 15 patients presented poor outcome. 48 h-NIHSS was higher in patients with HG during OT (15 versus 3; P<0.001). Patients with favorable outcome had shorter OT (8.4 versus 17.4 h; P<0.001). However, the only independent predictor of poor outcome was HG during OT (OR: 20.3; 95% CI: 3.77 to 108.8; P<0.001). At 24 h mean DWg was 52 cm(3). A receiver operating characteristic curve identified DWg>14 cm(3) best predictor of poor outcome (sensitivity, 85.7%; specificity, 75%). Total OT (P=0.007) and HG during OT (P=0.01) showed the strongest correlation with DWg. DWI lesion grew 2.7 times faster in patients with HG than without HG during OT (1.73 versus 4.63 cm(3)/h of occlusion; P=0.07). In a regression model the only independent predictor of DWg was HG during OT (OR: 10.83; 95% CI: 1.96 to 59.83; P=0.006). Hyperglycemia, especially during OT, has a powerful deleterious effect after stroke accelerating brain damage.