3549 Background: Several studies tried to address the question of whether primary site of CRC could affect the outcome. Those analyses were limited by small sample size numbers and/or high degree of heterogeneity in stage and received treatments and/or limited information regarding molecular and pathologic features. Mucinous histology and BRAF mutations are more frequent in right-sided tumors and are both associated with worse outcome in the metastic setting. Methods: the analysis was conducted on a database of 455 mCRC prospectively enrolled in a pharmacogenetic translational study. Patients (pts) were treated with FOLFIRI/bevacizumab. Pts were excluded if data regarding mucinous histology and/or BRAF mutational status were lacking or if affected by synchronous right and left-sided tumors. Results: 200 pts were identified and included in the study. Mucinous histology, BRAF mutation and right-side primary were found in 35 (17.5%), 14 (7%) and 56 (28%) patients respectively. Right-side tumors were more frequently BRAF mutated (p<0.001) and the association was still significant when adjusting for mucinous histology (p=0.001). There was a trend in the association between mucinous and side (p=0.082). At a multivariate analysis, pts with right-side primary were at higher risk of progression (HR=1.88 [95%CI: 1.25-2.84], p=0.0026) and death (HR=2.07 [95%CI: 1.23-3.49], p=0.006). At a prespecified analysis in the subgroup of non-mucinous and BRAF wild-type tumors, pts with right-side primary achieved median PFS and OS of 10.0 and 28.9 mos compared to 13.0 and 47.6 mos of left-side (PFS, right vs left: HR=1.87 [95%CI: 1.19-2.91], p=0.003; OS: HR=1.91 [95%CI: 1.07-3.39], p=0.022). This was again confirmed in a multivariate model. Conclusions: These data underline a possible strong impact of side on the outcome of mCRC treated with first-line FOLFIRI plus bevacizumab. To give a biological explanation for these results, a GWAS on germinal DNA and gene-expression analyses on tumors are ongoing. In order to clarify the prognostic vs predictive role to antiangiogenic treatments of this feature analyses from 2 phase III randomized trials have been planned.