E15110 Background: Recent data from patients with metastatic disease enrolled on trials of systemic chemotherapy have suggested that the sidedness of colorectal cancer(CRC) is associated with survival differences with better response seen with right sided tumours. The biological explanation for these differences has not been confirmed and there have been concerns that the differences relate predominantly to patient selection in clinical trial design. This study examines survival differences by side in sequential patients with newly diagnosed, operable CRC. Methods: Data for 3281 consecutive patients from the Northern Sydney Local Health District from 1998 to 2012 who underwent surgical resection of their CRC were retrospectively collected. Survival was assessed by log-rank test, association between sidedness and tumor biology by chi squared analysis and multivariate analysis by Cox regression. Results: Overall, there was a survival difference between left and right sided colon cancer and rectal cancer (p < 0.022). However, stage for stage, only stage 3 patients demonstrated a survival difference with right sided colon cancers (median OS 67.1 months, p = 0.009) but not left sided colon cancers (70.4 months p = 0.132) having inferior survival compared to rectal cancers (83.2 months). In terms of biological associations, right sided tumors were more associated with advanced age (p < 0.001), female gender (p < 0.001), more advanced T and m stage (p < 0.001), high grade (p < 0.001), thin walled vessel invasion (p < 0.001), discontinuous extratumoral nodules (DETN) (p < 0.001), peritumoral lymphocytic response (p = 0.002), BRAFV600E mutation (p < 0.001), mismatch repair deficiency (p < 0.001), low lymphocyte-to-monocyte ratio (LMR) (p < 0.001) and high neutrophil-to-lymphocyte ratio (p < 0.001). In multivariate analysis, age (p < 0.001), T stage and m stage (p = 0.001), grade (p = 0.002), extra venous permeation(p = 0.034), DETN (p = 0.09), MMR-BRAF combined status (p = 0.001) and LMR (p < 0.001) remained independently significant. Conclusions: There appears to be a difference in survival related to tumor site only in stage 3 CRC. Differences in tumor biology could account for these findings.