Background: Th17 cells constitute a subset of T-helper cells, and play a role in immune response to extracellular pathogens in the human intestinal tract. Further, Th17 cells are associated with tumor angiogenesis and enhanced efficacy of 5-FU treatment. We thus investigated associations between the Th17 cell pathway-related SNPs and clinical outcomes in patients with metastatic colorectal cancer (mCRC) treated with conventional chemotherapy. Methods: We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC, and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6, or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). Multivariable logistic regression and Cox regression were performed to evaluate the association between candidate SNPs in the Th17 cell pathway and clinical outcomes [tumor response (TR), progression-free survival (PFS), and overall survival (OS)] in each treatment cohort. The meta-analysis approach using the METASOFT software were implemented to quantify the prognostic effect of each SNP using the inverse-variance-weighted effect size, and also to evaluate the heterogeneity across cohorts using the Q statistic. SNPs were coded as additive, dominant, or recessive in the analysis. The Pegasus analysis was also used to identify effects across multiple SNPs and treatment arms. Results: Pathway analysis showed that the Th17 cell pathway was significantly associated with TR (P = 0.011). There were suggestive associations of IL17F rs763780 with TR (log OR = 0.64, SE = 0.31; P = 0.038), of IL23R rs10889677 with TR (log OR = 0.37, SE = 0.18; P = 0.039), of IRF4 rs872071 with TR (log OR = -0.26, SE = 0.13; P = 0.037), and of IL21 rs2221903 with PFS (log HR = 0.33, SE = 0.15; P = 0.026), although these results were not significant after FDR adjustment. In addition, IL23R rs10889677 had suggestive heterogeneity of effects for PFS across the six cohorts after Cochran’s Q statistic (P = 0.013). Conclusions: Th17 cell pathway-related SNPs may be predictors for the first-line chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies for mCRC.