Perihematomal edema (PHE) can worsen patient outcomes after spontaneous intracerebral hemorrhage (ICH). Minimally invasive surgery (MIS) in combination with thrombolytic removal of hematoma has been proven to be a promising treatment strategy. However, preclinical studies have suggested that intraclot thrombolysis may exacerbate PHE after ICH. Herein, we investigated the effects of MIS and urokinase on PHE. ICH patients were retrospectively identified from our institutional ICH database. Computerized volumetric analysis was applied to assess changes in both ICH and PHE volumes using computed tomographic (CT) scans of T-1 (pre-MIS) and T-2 (post-MIS) time points. Relative PHE (rPHE) was calculated as a ratio of PHE and T-1 ICH volume. Data from 60 MIS plus urokinase (MIS + U), 20 MIS aspiration only (MO), and 30 control patients were analyzed. The ICH volume, PHE volume and rPHE on T-2 CT in both MIS + U and MO groups significantly decreased as compared with the control group (ICH volume, 13.7 +/- 5.7 ml, 17.0 +/- 10.5 ml vs. 30.5 +/- 10.3 ml, P < 0.01; PHE volume, 36.5 +/- 18.9 ml, 32.2 +/- 17.5 ml vs. 45.4 +/- 16.0 ml, P < 0.01; rPHE, 0.9 +/- 0.4, 0.8 +/- 0.4 vs.1.4 +/- 0.5, P < 0.01). Between the MIS + U and MO groups, the ICH volume, PHE volume and rPHE at T-2 trended towards similarity, but was not significant (P = 0.09, P = 0.40, P = 0.43). Furthermore, we found a significant correlation between the percent of ICH removal and PHE reduction (r = 0.59, P < 0.01). There was no correlation between the cumulative dose of urokinase and either T-2 PHE volume (r = 0.19; P = 0.16) or T-2 rPHE (r = -0.12; P = 0.37). Hematoma evacuation using MIS leads to a significant reduction in PHE. Furthermore, the use of urokinase does not exacerbate PHE, making its hypothesized proedematous effects unlikely when the thrombolytic is administered directly into the clot.