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Introduction: Galectin-3 is a beta-galactoside-binding protein expressed in many types of human cells including epithelial and immune cells. Gal-3 is synthesized in the cytoplasm as a cytosolic protein but is found in a variety of locations within the cell. Cytoplasmic Gal-3 functions as an apoptosis inhibitor while nuclear Gal-3 has pro-apoptotic activity. Loss of Gal-3 in the nucleus and its accumulation in the cytoplasm is commonly seen in a variety of human cancers including colorectal and prostate carcinoma; these changes also correlate with angiogenesis as well as tumor invasion and progression. Gal-3 is believed to be a mediator of VEGF’s and bFGF’s pro-angiogenic effects. Gal-3 is also found in the blood in a soluble form where it acts as a ligand. Increased blood levels of soluble Gal-3 (sGal-3) have been noted in patients (pts) with breast, lung, and head and neck cancers but its levels in colorectal cancer (CRC) pts have not been well studied. This study’s purpose was to compare preoperative (PreOp) plasma sGal-3 levels in CRC and benign colon disease pts. Methods: Pts undergoing colorectal resection for CRC or benign problems that had been prospectively enrolled in an IRB approved tissue and data bank for whom adequate Preop plasma samples were available were studied. Demographic, clinical, operative, and pathologic data were collected. The Gal-3 levels in the preoperative plasma samples were determined via ELISA in duplicate and reported as mean ± SD. The t-test was used to compare the results of the 2 groups (significance p<0.05). Results: A total of 83 CRC (77% colon, 23% rectal) and 71 benign disease pts (adenoma 39%, diverticulitis 61 %) were studied. The male:female ratio’s were similar but the CRC pts were older (p=0.001). In the CRC group the stage distribution was: stage 1, 22 (31%); stage 2, 27 (36%); stage 3, 24 (23%); stage 4, 10 (10%). The mean PreOp plasma sGal-3 level was significantly higher in the CRC group than in the benign disease group (13.6±7.8 ng/ml vs. 8.3±3.4 ng/ml, p<0.0001). No correlation was found between sGal-3 levels and tumor stage. Conclusion: The mean Preop plasma sGal-3 level was 63.8% higher in the CRC vs. the benign disease group (p<0.0001), which is notable. Although not proven, the source of the added Gal-3 in the plasma of CRC pts may be the tumor cells, stromal cells, and inflammatory cells surrounding the cancer. Higher sGal-3 levels may be related to neovascularization and inflammation-induced tissue remodeling at tumor sites. Further studies with a larger population of healthy control and CRC pts are needed to better determine if there is a correlation between plasma sGal-3 levels and cancer stage or progression. sGal-3 holds some promise as a prognostic marker.