Proteomics plays a pivotal role in clinical diagnostics and monitoring. We conducted proteome-wide Mendelian randomization (MR) study to estimate the causal association between plasma proteins and Herpes simplex virus (HSV) infection. Data for 2,923 plasma protein levels were obtained from a large-scale protein quantitative trait loci study involving 54,219 individuals, conducted by the UK Biobank Pharma Proteomics Project. HSV-associated SNPs were derived from the FinnGen study, which included a total of 400,098 subjects infected with HSV. MR analysis was performed to assess the links between protein levels and the risk of HSV infection. Furthermore, a Phenome-wide MR analysis was utilized to explore potential alternative indications or predict adverse drug events. Finally, we evaluated the impact of 1,949 plasma proteins on HSV infection, identifying 48 proteins that were negatively associated with HSV infection and 54 proteins that were positively associated. Genetically higher HLA-E levels were significantly associated with increased HSV infection risk (OR = 1.39, 95% CI: 1.17-1.65, P = 2.13 × 10