BACKGROUND AND PURPOSE: Previous data have shown the feasibility of identifying ischemic penumbra in patients with acute stroke by using a semiautomated analysis of ADC maps. Here, we investigated whether the fate of ADC-defined penumbra was altered by HG. We also examined the interaction between HG and arterial recanalization on infarct growth. MATERIALS AND METHODS: We examined 94 patients by using MR imaging within 6 hours of stroke onset and a follow-up MR imaging within 7 days. The ADC-defined tissue-at-risk was calculated from the early MR imaging. Patients were classified according to high (>7 mmol/L; n = 34/94, HG) or normal (n = 60/94) baseline SGL. The impact of HG status on infarct growth was assessed by using multiple regression models and analysis of the slopes of regression lines for each group. Interaction between HG status and arterial recanalization on infarct growth was investigated by using multiple regression analysis. RESULTS: The slope of the predicted versus observed infarct growth regression line was steeper in HG than non-HG patients (P = .0008), suggesting that infarct growth within ADC-defined tissue-at-risk was increased in HG patients. The effect was 2.8 times more severe in nonrecanalized patients (P = .01) than in patients with recanalization (P = .001). CONCLUSIONS: ADC-defined tissue-at-risk may represent ischemic penumbra because part of this area may be salvaged in normal SGL patients. The toxicity in HG patients seems to be more related to penumbra-infarction transition than reperfusion injury in humans because the effect was larger in nonrecanalized than in recanalized patients.