Background Immune-checkpoint blockade has shown anti-tumor activity in MSI mCRC patients only, thus, the research of more efficacious immunological strategies for colon cancer treatment is still open. GOLFIG, is a safe and active chemo-immunotherapy regimen designed on the basis of preclinical immune-oncological findings and evaluated in two subsequent Phase II and III trials in mCRC patients (J Clin Oncol, 2005,23:8950; J Immunother, 2014;37:26). This regimen combines gemcitabine + FOLFOX poly-chemotherapy with salgramostim (GM-CSF) and low dose sc. aldesleukin, to improve both cross-priming and T-cell effector anti-tumor response. Here we report a fifteen-year retrospective analysis of all patients undergone this therapeutic approach. Methods This is a multi-institutional real-life study including one hundred-seventy-nine mCRC patients receiving GOLFIG regimen between October 2001 and November 2018 with a median follow up of 120 months. The treatment was administered to 62 patients (GOLFIG-2 trial, EUDRACT: 2005-003458-81) as a first-line and to 117 patients as second/third-line (49 enrolled in the GOLFIG-1 phase II trial and 68 as real life). Kaplan-Meier and Cox-regression were carried-out to relate their PFS and OS with sex, age, sidedness, RAS mutational status, previous treatment lines, baseline clinical parameters and treatment-related irAEs. Results We recorded a PFS and OS of 15.3 (95%CI:10.4-20.2) and 24.6 (95%CI:19.07-30.14) months, respectively, with 10% of the patients surviving more than ten years. Patients’ outcome did not correlate with sex, sidedness and RAS. First line GOLFIG confirmed superiority over FOLFOX in term of PFS (HR = 0.58 p = 0.006) and OS (HR = 0.69, P = 0.06) (updated from GOLFIG-2 trial). Patients in first-line showed a longer PFS (HR = 0.69; p = 0.041) compared with the others, with no difference in OS. On the overall, a longer PFS and OS correlated with baseline neutrophil counts ≤ 4,500 cells/µl (HR:0.32; P = 0.003) and occurrence of irAEs (HR = 0.36; P = 0.0001) recorded in 24% of the cases. Conclusions These results confirm that the GOLFIG regimen is a reliable therapy for pretreated mCRC patients and offer the rationale to design combination trials with immune-checkpoint blockade. Clinical trial identification 1) GOLFIG-2 phase III trial; EudraCT: 2005-003458-81 2) GOLFIG-1 phase II trial; EudraCT no available, start July 2001. Legal entity responsible for the study The authors. Funding Italian Ministry of Education and Research (MIUR) (2009EHW394). Private grant from the “Associazione Culturale Federico II,” and from the “Associazione Riuniti Calabria Oncologia (ARCO)”. Disclosure All authors have declared no conflicts of interest.