The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator (rt-PA) on perihematomal edema (PHE) development in patients with intracerebral hemorrhage (ICH) treated with minimally invasive surgery (MIS) and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS (T-1), post-MIS (T-2) and day 10-16 (T-3) following diagnostic computed tomographic scans (T-0). Forty-three patients aged 52.8 +/- 11.1 years with (n=30) or without rt-PA (n=13) were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 (1) mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls (77.9%+/- 20.4% vs. 64%+/- 15%; P=0.046). From T-1 to T-2, reduction in PHE volume was strongly associated with the percentage of clot evacuation (rho=0.34; P=0.027). In addition, PHE volume was positively correlated with residual ICH volume at the same day (rho ranging from 0.39-0.56, P < 0.01). There was no correlation between the cumulative dose of rt-PA and early (T-2) PHE volume (rho=0.24; P=0.12) or delayed (T-3) PHE volume (rho=0.19; P=0.16). The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mortality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.