We have previously demonstrated that open surgical trauma induces rapid depletion of an important cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3). The aim of the current study was to identify a mechanism to account for the rapid proteolysis of IGFBP-3 that occurs postoperatively. Methods: Eighty one stage I-III colorectal adenocarcinoma patients were included; 33 had open surgery (OS) and 48 laparoscopic-assisted resection (LS). Mean incision size was 18.5±5.6 cm for the OS and 5.2±1.7 cm for the LS group. Peripheral blood was collected preoperatively (pre-OP) and on postoperative days (POD) 1-3. Plasma proteolytic activity was studied via zymography. Serum MMP-9 levels were subsequently measured in ELISA. MMP-9 expression in peripheral blood mononuclear cells (PBMC) was studied by intracellular staining, sub-cellular localization of MMP-9 was performed by staining ethanol fixed cells with FITC labeled anti-MMP-9 antibody followed by analysis with confocal microscopy. The effect of LPS stimulation on MMP-9 release by PBMC in vitro was also assessed. Statistical analysis was performed via the Wilcoxon's test. Results: The most prominent plasma protease, size 92 kDa, corresponded to the pro-form of MMP-9; this was confirmed in Western Blot analysis using antibody to MMP-9. MMP-9 is known to cleave IGFBP-3. The mean MMP-9 level in OS patients increased on POD1 (359.9±202.5 ng/ml) compared to pre-OP (221.6±170.6 ng/ml, p<0.006), but returned to normal on POD2-3. In the LS group the MMP-9 levels on POD1 (249.4±267.3 ng/ml) were comparable to pre-OP levels (246.2±172.0 ng/ml). Monocytes were identified as a major source of MMP-9 in PBMC. MMP-9 protein was localized in cytoplasmic granules of monocytes and released in response to LPS stimulation in vitro. Conclusions: OS trauma induces a rapid increase in serum MMP-9 levels. Monocytes store MMP-9 in cytoplasmic granules and rapidly release this protease in response to LPS, a pro-inflammatory stimulus. This effect is short lived, but may play a role in the early postoperative degradation of the important cell growth regulatory proteins, such as IGFBP-3.