Background A better understanding of the association between liver MRI proton density fat fraction (PDFF) and liver diseases might support the clinical implementation of MRI PDFF. Purpose To quantify the genetically predicted causal effect of liver MRI PDFF on liver disease risk. Materials and Methods This population-based prospective observational study used summary-level data mainly from the UK Biobank and FinnGen. Mendelian randomization analysis was conducted using the inverse variance-weighted method to explore the causal association between genetically predicted liver MRI PDFF and liver disease risk with Bonferroni correction. The individual-level data were downloaded between August and December 2020 from the UK Biobank. Logistic regression analysis was performed to validate the association between liver MRI PDFF polygenic risk score and liver disease risk. Mediation analyses were performed using multivariable mendelian randomization. Results Summary-level and individual-level data were obtained from 32 858 participants and 378 436 participants (mean age, 57 years ± 8 [SD]; 203 108 female participants), respectively. Genetically predicted high liver MRI PDFF was associated with increased risks of malignant liver neoplasm (odds ratio [OR], 4.5; P < .001), alcoholic liver disease (OR, 1.9; P < .001), fibrosis and cirrhosis of the liver (OR, 3.0; P < .004), fibrosis of the liver (OR, 3.6; P = .002), cirrhosis of the liver (OR, 3.8; P < .001), nonalcoholic steatohepatitis (OR, 7.7; P < .001), and nonalcoholic fatty liver disease (NAFLD) (OR, 4.4; P < .001). Individual-level evidence supported these associations after grouping participants based on liver MRI PDFF polygenic risk score (all P < .004). The mediation analysis indicated that genetically predicted high-density lipoprotein cholesterol, type 2 diabetes mellitus, and waist-to-hip ratio (mediation effects, 25.1%-46.3%) were related to the occurrence of fibrosis and cirrhosis of the liver, cirrhosis of the liver, and NAFLD at liver MRI PDFF (all P < .05). Conclusion This study provided evidence of the association between genetically predicted liver MRI PDFF and liver health. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Reeder and Starekova and Monsell in this issue.