Background: Frailty is closely related to cancer. Previous research has shown that cancer patients are prone to frailty, and frailty increases the risk of adverse outcomes in cancer patients. However, it is unclear whether frailty increases the risk of cancer. This 2-sample Mendelian-randomization (MR) study sought to analyze the relationship between frailty and the risk of colon cancer. Methods: The database was extracted from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) in 2021. The genome-wide association study (GWAS) data related to colon cancer was obtained from the GWAS website (http://gwas.mrcieu.ac.uk/datasets), involving 462,933 individuals' gene information. Single-nucleotide polymorphisms (SNPs) were defined as the instrumental variables (IVs). The SNPs closely associated with the Frailty Index at a genome-wide significance level were selected. To further screen the IVs, we selected the confounding factors using the PhenoScanner (http://www.phenoscanner. medschl.cam.ac.uk/phenoscanner). To estimate the causal effect of the Frailty Index on colon cancer, the MR-Egger regression, weighted median (WM1), inverse-variance weighted (IVW), and weight mode (WM2) methods were applied to calculate the SNP-frailty index and the SNP-cancer estimates. Cochran's Q statistic was used to estimate heterogeneity. The two-sample Mendelian randomization (TSMR) analysis was performed using the "TwoSampleMR" and "plyr" packages. All the statistical tests were 2-tailed, and a P value <0.05 was considered statistically significant. Results: We selected 8 SNPs as the IVs. The results of the IVW analysis [odds ratio (OR) =0.995, 95% confidence interval (CI): 0.990-1.001, P=0.052] showed that the genetic changes in the Frailty Index were not statistically associated with the risk of colon cancer, and no significant heterogeneity between these 8 genes was observed (Q =7.382, P=0.184). The MR-Egger (OR =0.987, 95% CI: 0.945-1.031, P=0.581), WM1 (OR =0.995, 95% CI: 0.990-1.001, P=0.118), WM2 (OR =0.996, 95% CI: 0.988-1.004, P=0.356), and SM (OR =0.996, 95% CI: 0.987-1.005, P=0.449) results were also consistent with each other. The sensitivity analysis based on the leave-one-out method showed that the individual SNPs did not affect the robustness of the results. Conclusions: Frailty might have no effect on the risk of colon cancer.