Background: The immunoglobulin G1 (IgG(1)) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG(1) may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (Fc gamma R) polymorphisms. We investigated the association of Fc gamma R polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab. Patients and methods: Tumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fc gamma RIIa and Fc gamma RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p - 0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an Fc gamma RIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p = 0.017). By multivariate analysis, Fc gamma RIIa-131H/H remained significantly correlated with DCR (p = 0.008). Conclusion: Fc gamma R polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted. (C) 2012 Elsevier Ltd. All rights reserved.