Hepatocyte proliferation and apoptosis are major features of hepatic regeneration after partial hepatectomy (hep). Matrix remodeling is also important in this process; recent studies have shown increases in matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 in the context of partial hep and liver regeneration. We postulated that MMP's may be important in the hepatic regenerative process after partial hep. To investigate this hypothesis, MMP-9's effects on hepatocyte proliferation and apoptosis after 70% hep was studied using MMP-9 knock out (ko) mice. Wild type (WT) or MMP-9ko mice underwent 70% hep or sham laparotomy and were sacrificed on post-operative day 2, 3, or 5. Liver wt/total body wt ratios and BrdU staining were measured as estimates of hepatocyte proliferation; TUNEL staining measured hepatocyte apoptosis. Liver wt/total body wt ratios in the MMP-9ko mice were lower than WT after hep at all time points; this was statistically significant on day 5 (MMP-9ko: 2.68±0.08 vs WT: 3.06±0.08, p<0.05). There were no significant differences noted in the sham operated controls. BrdU staining confirmed a slower and more prolonged period of hepatocyte proliferation in MMP-9ko versus WT mice after hep. This was significant on day 2 (MMP-9ko: 117.5±19.3 BrdU+cells/LPF vs WT: 191.1±21.4 BrdU+cells/LPF, p<0.05) and day 3 (MMP-9ko: 100.2±13.9 BrdU+cells/LPF vs WT: 35.5±3.5 BrdU+cells/LPF, p<0.05). TUNEL staining also showed a slower onset and lower magnitude of apoptosis in ko mice as compared to WT after hep. This was significant on day 5 (MMP-9ko: 59±9 TUNEL+cells/LPF, WT: 108±4 TUNEL+cells/LPF, p<0.05). This suggests that both proliferation and apoptosis are influenced by MMP-9 and matrix remodeling. Next, NF-KB expression in the hepatic cytosolic and nuclear fractions of ko and WT mice after hep was measured by Western blot. A delay in NF-KB expression in ko's versus WT's was seen, suggesting that the observed delays in hepatocyte proliferation and/or apoptosis are mediated via NF-KB signaling. These data suggest that the matrix remodeling process, particularly related to MMP-9, is important in liver regeneration following partial hepatectomy; this process may be controlled at least in part by NF-KB signal transduction mechanisms.