Background: FOLFOXIRI/bev is a valid option as first-line therapy for unresectable mCRC. TRIBE and TRIBE2 trials reported better activity and efficacy of the triplet/bev when compared with doublets/bev at the price of a higher incidence of chemo-related toxicities, including neutropenia (N). Here we aim at providing a detailed description of this adverse event, including the occurrence of febrile neutropenia (FN) and the use of granulocyte-colony stimulating factors (G-CSFs), in order to estimate the clinical relevance of N during FOLFOXIRI/bev. Methods: Safety data of 1175 pts enrolled in the TRIBE and TRIBE2 studies were reviewed. The incidence of N, the incidence and severity of FN, and the use of G-CSF in the triplet/bev and in the doublets/bev arms were compared using the Chi-square or the Fisher exact test as appropriate. Results: Out of 1175 pts included in the final analysis, 586 (49.8%) were treated with FOLFOXIRI/bev. Five pts (0.8%) in the doublets/bev arms and 29 (4.9%) in the triplet/bev arms received a primary prophylaxis with G-CSF. Among other pts, 118 (20.2%) in the doublets/bev arms and 276 (49.9%) in the triplet/bev arms experienced ≥ G3 N (p < 0.001). FN occurred in 25 (4.3%) and 41 (7.4%) cases respectively (p=0.041). Out of 78 FN episodes, 4 (13.3%) out of 30 in the doublets/bev arms and 13 out of 48 (27.1%) in the triplet/bev arms were associated with a poor MASCC score (<21) (p=0.17). G-CSF was used in 1069 (10.8%) cycles, 270 (5.3%) in doublets/bev and 799 (16.6%) in triplet/bev arms. In both arms, the majority of N and FN episodes were observed in the first two months (318 ≥ G3 N episodes out of 675 (47.1%), and 54 FN episodes out of 78 (69.2%)). Conclusions: FOLFOXIRI/bev was associated with a higher risk of N and FN than doublets/bev. However, the risk of FN was lower than 10%, thus not requiring a systematic use of primary G-CSF prophylaxis. The majority of FN episodes was associated with a good MASCC score, thus having a limited clinical impact. The vast majority of FN episodes occurred in the first two months of treatment, suggesting a closer monitoring of this adverse event during the first courses of therapy.