Background: CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with Bev, Cet, or both, plus chemotherapy. No difference in OS was found between Bev and Cet. We tested the effect of immune signatures on OS in all the three arms of the study and analyzed differences in OS between the Cet and Bev arms. Methods: 578 primary tumors were profiled by RNAseq. Immune signatures of TGF-β, cytotoxic T cells, wound healing, macrophages, lymphocytes, and INF-γ, as well as relative frequencies of CD8+ T-cells, memory resting CD4+ T cells, memory activated CD4+ T cells, macrophages M1 and M2, and activated mast cells were measured. Multivariate Cox proportional hazard models were applied using elastic-net penalization with covariates (age, race, gender, all RAS and BRAF V600E mutations). For relevant signatures, optimal cut-offs for OS were calculated. Results: In all the three arms of the study, high expression of macrophages M2 (HR 6.81, 95% CI 3.56-30.16) and TGF-β (HR 1.37, 95% CI 1.03-2.10) conferred reduced OS compared to low expression; high expression of plasma cells (HR 0.52, 95% CI 0.27-0.83) and memory-activated CD4+ T cells (HR 0.34, 95% CI 0.10-0.65) conferred increased OS compared to low expression. Using optimal cut-offs from these 4 signatures, pts have been categorized as to whether they had either 4, 3, 2, 1, or 0 beneficial signatures associated with increased OS. In all arms of the study (N = 469, after accounting for covariates), the median (95% CI) OS decreased from 42.5 (35.8-47.8; N = 79), to 31.0 (28.8-34.4; N = 177), 25.2 (20.6-27.9; N = 144), and 17.0 (13.5-20.4; N = 69) months when the number of beneficial signatures decreased from 4, to 3, 2, and 0-1 (combined due to a low number of pts), respectively (p = 3.48e-11). In the Bev arm (N = 205), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 6.6, 95% CI 2.7-67.1). In the Cet arm (N = 165), high expression of macrophages M2 conferred reduced OS compared to low expression (HR 4.3, 95% CI 2.1-79.8); high expression of plasma cells (HR 0.36, 95% CI 0.06-0.55) and memory activated CD4+ T cells (HR 0.37, 95% CI 0.03-0.98) conferred increased OS compared to low expression of either signatures. The plasma cell signature interacted with Bev and Cet on the OS of pts (interaction p = 0.009). Conclusions: Tumor immune signatures in mCRC pts are determinants of survival. In pts treated with Bev- and Cet-combination therapies that are standard of care, immune signatures affect response to therapy. These results, provide new markers for treatment selection and for the development of novel active combinations including immune checkpoint inhibitors. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org