OBJECTIVE: Several observational studies have identified an association between plasma proteins and hepatocellular carcinoma (HCC). This study aimed to explore the potential causal relationship between the circulating protein-to-protein ratio and the morbidity risk of HCC. METHODS: Genetic association data for circulating plasma proteins and 2821 protein-to-protein ratios were sourced from the UKB PPP and Suhre's study. Genetic association data for HCC were sourced from the FinnGen cohort (finngen-R11-HCC) and the IEU OpenGWAS project (ieu-b-4953). Subsequently, a two-sample Mendelian randomization (MR) and drug-targeted MR approach were used to evaluate causality associations. To bolster the robustness of our findings, we conducted a series of sensitivity analyses. RESULTS: Eight protein-protein pairs were identified as causal factors for HCC in the two independent cohorts. For each standard deviation increase in protein-protein pair expression, susceptibility to HCC fluctuated from 0.4974 (95% confidence interval [CI]: 0.2506-0.9871) for the LAT2/SPRY2 protein pair to 1.9763 (95% CI: 1.3009-3.0026) for the ERBIN/LAT2 protein pair. However, among the significant protein pairs, only one circulating protein, TDRKH (odds ratio: 0.5964, 95% CI: 0.4196-0.8476), was causally associated with HCC. CONCLUSION: Using multiple datasets and methods, eight protein-protein pairs were identified as having causal associations with HCC. Protein-protein interactions can provide meaningful findings beyond simple pQTL analysis.