Background <p>The pathogenesis of hepatocellular carcinoma (HCC) involves a variety of environmental risk factors, some of which have yet to be fully clarified. Using the Mendelian randomization (MR) approach, this study comprehensively investigates the causal effect of genetically predicted modifiable risk factors on HCC.</p> Methods <p>Genetic variants related to the 50 risk factors that had been identified in previous research were derived from genome-wide association studies. Summary statistics for the discovery cohort and validation cohort of HCC were sourced from the FinnGen consortium and the UK Biobank, respectively. Bidirectional MR analysis and sensitivity analysis were performed to establish causative risk factors for HCC.</p> Results <p>Through the inverse variance weighted method, the results of the discovery cohort indicated that waist circumference, nonalcoholic fatty liver disease (NAFLD), alanine aminotransferase (ALT) levels, and aspartate aminotransferase (AST) levels were significantly linked to HCC occurrence risk. Furthermore, body fat percentage, glycated hemoglobin (HbA1c), obesity class 1–3, waist-to-hip ratio, iron, ferritin, transferrin saturation, and urate had suggestive associations with HCC. The validation cohort further confirmed that NAFLD and ALT levels were strongly related to HCC. Reverse MR indicated that genetic susceptibility to HCC was connected to NAFLD and transferrin saturation. Sensitivity analyses showed that most of the findings were robust.</p> Conclusion <p>This MR study delivers evidence of the complex causal relationship between modifiable risk factors and HCC. These findings offer new insights into potential prevention and treatment strategies for HCC.</p>