Background: The role of IV heparin in acute ischemic stroke (AIS) is controversial. We investigated the effect of IV heparin on ischemic lesion growth. Methods: We analyzed data on 274 consecutive AIS patients with non-lacunar stroke prospectively enrolled in a study where diffusion/perfusion MRI (DWI-PWI) was completed <12 hrs after last seen well and a follow-up MRI/CT completed after day 4. We excluded patients treated with tPA, and those with MTT-DWI mismatch <20% of the DWI volume or absolute mismatch volume <10 mL. Lesion growth was assessed by (a) Absolute Lesion Growth , i.e. final infarct volume - admission DWI lesion volume, and (b) Percentage mismatch lost (PML) , i.e. (final infarct volume - admission DWI volume)/(mismatch volume)x100%. Image analysis was blinded to clinical data. Univariable and multivariable analysis were performed to determine the effects of IV heparin on infarct growth. Results: N=113 met inclusion/exclusion criteria; 52 received IV heparin shortly after admission. Results of the univariable analysis are shown in Table 1. Heparin use was associated with smaller PML (p<0.05); there was approximately 5-fold difference in PML between heparin users and non-users. Absolute lesion growth was significantly associated with admission glucose, blood pressure, NIHSS score, DWI volume and stroke etiological subtypes; and there was a trend for association with age and heparin use. Intravenous heparin use was an independent predictor of both PML and absolute lesion growth (Table 2), and was associated with better 3-month outcomes (modified Rankin scale score 0-2, 80% vs. 57%, p=0.04). Conclusion: These data suggest that IV heparin administration early after stroke may attenuate the progression of ischemic brain injury in non-thrombolyzed patients with significant ischemic penumbra.