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Previous studies suggest that granulocyte colony-stimulating factor (G-CSF) drugs may increase the risk of certain cancers, but findings remain controversial. We employed a drug-target Mendelian randomization approach to investigate the causal relationship between G-CSF and 14 cancer types. The target gene of G-CSF drugs was sourced from the DrugBank database. Expression quantitative trait loci data for the target gene (CSF3R) were obtained from the expression quantitative trait loci Gen Consortium. Genome-wide association study data for the 14 cancers were retrieved from the FinnGen dataset. A Bonferroni correction was applied for multiple testing (P < .0036). Analyses were performed using the inverse variance weighted, Mendelian randomization-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analyses were conducted to verify the reliability of the findings. Inverse variance weighted analysis revealed a significant association between genetically proxied G-CSF exposure and an increased risk of lung squamous cell carcinoma (LUSC) [odds ratio: 1.61, 95% confidence interval: 1.20-2.17, P = 1.51 × 10-3] and a potential association with estrogen receptor-negative breast cancer (odds ratio: 1.26, 95% confidence interval: 1.06-1.50, P = 7.31 × 10-3). The association with LUSC remained significant after multiple testing correction. No statistically significant associations were found with the other 12 cancers. Sensitivity analyses indicated no evidence of heterogeneity or pleiotropy. While these results suggest a potential causal role of G-CSF in the development of LUSC and possibly estrogen receptor-negative breast cancer, their clinical implications (particularly regarding long-term G-CSF use) should be interpreted with caution. Further validation in large-scale prospective studies and diverse populations is essential before any clinical recommendations can be made. Our findings highlight the need for continued investigation into the long-term safety profiles of G-CSF and may contribute to a more nuanced understanding of its risk-benefit balance in specific clinical contexts.