Serum active matrix metalloproteinase (MMP)-9 and -2 levels and their tissue inhibitors TIMP-1 and -2 were measured in 28 patients with spontaneous intracerebral hemorrhage (SICH) at 24 h, 48 h and 7 days after bleeding. Perihematomal edema volume was calculated on non-enhanced computed tomography scans by using the formula AxBxC/2 at the same time points. Mean levels of serum active MMP-9 and MMP-2, as well as perihematomal edema volume, were significantly different over time (p < 0.0001). In comparison to values observed at 24 h, serum active MMP-9 mean concentrations increased at 48 h and reached their peak at 7 days, serum active MMP-2 mean levels progressively declined at 48 h and at 7 days, whereas perihematomal edema volume increased at 48 h and at 7 days. Perihematomal edema volume was positively correlated with active MMP-9 and MMP-2 at 24 h (p < 0.02 and p < 0.05, respectively) and with active MMP-9 at 48 h (p < 0.05), but was inversely correlated with active MMP-2 at 7 days (p < 0.02). These findings suggest a different involvement of active MMP-9 and MMP-2 in perihematomal-associated inflammatory response occurring in the transition from acute to subacute phases after SICH.