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Background and Purpose: Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it., Methods: Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans., Results: Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm(3) for the surgical cohort and 40.7±13.9 cm(3) for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm(3) than medical cohort: 41.7±14.6 cm(3) (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm(3); and surgical aspiration only, 24.5±14.0 cm(3) (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm(3) and 24.4±8.6 cm(3) in surgical aspiration only (P=0.41)., Conclusions: Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.