Abstract Background: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5fluoruracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of metastatic colorectal cancer (mCRC) patients, with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune-checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. Methods: mCRC patients unselected for MMR status were randomized(1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). RT-qPCR by DetermaIO was performed on RNA purified from pre-treatment tumours of 132(61%) out of 218 enrolled patients. A binary result (IOpos versus IOneg) adopting the pre-established DetermaIO cut-point (0.09) was obtained, and an exploratory optimized cut-point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos versus IOOPTneg). Results: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumours were IOpos. IOpos tumours achieved higher PFS benefit from atezolizumab arm than IOneg (HR:0.39 versus 0.83, P interaction=0.066). In pMMR tumours (N=110), a similar trend was observed (HR:0.47 versus 0.93, P interaction=0.139). In the overall population, with the computed IOOPT cut-point (0.277), 16 (13%) tumours were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg(HR:0.10 versus 0.85, P interaction=0.004). Similar results were found in the pMMR subgroup. Conclusions :DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-point should be validated in independent mCRC cohorts.