Abstract Background In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue ( KRAS ) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX folinic acid, 5-fluorouracil, and oxaliplatin or FOLFIRI folinic acid, 5-fluorouracil, and irinotecan. However no trial has directly compared these combinations. Methods Multicentre, open-label study in untreated patients ≥ 18 years with (WT)- KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT- RAS patients. Results Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT- RAS : 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT- RAS : 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT- RAS : 37%/69%). The R0-R1 resection rate was 34%/46% (WT- RAS :26%/54%). Median PFS was 13/14 months (hazard ratio HR Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: 0.6–1.5; WT- RAS :13/15; HR: 0.7 0.4–1.3). Median OS was 37/41 months (HR:1.0 0.6–1.8; WT- RAS : 39/49; HR:0.9 0.4–1.9). In WT- RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm. Conclusions In patients with WT- KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov: NCT00885885 ).