Background: Cet exerts its therapeutic effects not only through EGFR-signal blockade but also through antibody-dependent cell-mediated cytotoxicity (ADCC), mainly driven by natural killer (NK) cells. NK cells play a key role by releasing granzyme B (GZMB) via perforin (PRF1)-formed pores, leading to tumor cell apoptosis. CD137 (TNFRSF9) is expressed on NK cells, which regulates activation and proliferation of T cells. We hypothesized that genetic alteration in NK cell-mediated ADCC may serve as a predictor of cet in mCRC pts. Methods: Genomic DNA and RNA were isolated from tumor tissues of 77 KRAS exon2 wild-type (wt) pts enrolled in 2 Japanese phase II trials of cet plus oxaliplatin-based chemotherapy as 1st-line therapy, FOLFOX (n= 28/57, UMIN000004197) and SOX (n= 49/67, UMIN000007022). We evaluated associations between functional polymorphisms and gene expression of TNFRSF9, GZMB, and PRF1, and clinical outcome using PCR-based direct sequencing and molecular profiling panel (HTG EdgeSeq Oncology Biomarker Panel) based on next generation sequencing. Recursive partitioning (RP) method was also used to explore the associations. Results: In the population with median age of 63 years and follow-up time of 31.4 months (m), response rate (RR), median progression-free survival (PFS), and overall survival (OS) were 73 %, 10.0 m, and 33.9 m, respectively. TNFRSF9 rs161826 (A > G) was associated with PFS but not RR or OS in both univariate (any G vs A/A: 9.2 m vs 13.8 m, HR 1.75, P= 0.030) and multivariate analyses (P= 0.050). No association of rs161826 with gene expression was observed. PRF1 polymorphisms were not associated with outcome, while high PRF1 mRNA expression had association with shorter PFS (9.7 m vs 18.0 m, HR 2.60, P= 0.028), and it remained significant in multivariate analysis (P= 0.002). In RP analysis, PRF1 mRNA expression also showed significant association with PFS. Conclusions: TNFRSF9 rs161826 and PRF1 gene expression are significantly associated with PFS in pts with KRAS wt mCRC treated with cet-based chemotherapy. Gene expression and variation in NK cell-mediated ADCC may predict efficacy of cet (UMIN000010635). Clinical trial information: UMIN000010635.