AIM: To investigate the role of RNA methylation in retinal pigment epithelial (RPE) cells in age-related macular degeneration (AMD). METHODS: RNA methylation-related gene expression profiles of AMD patient and normal control retinal pigment epithelium were evaluated by single-cell transcriptome from 34 samples (11 from normal donors and 23 from AMD patients). The causal relationship between RNA methylation dysfunction and AMD was analyzed by summary-data-based Mendelian randomization (SMR) using AMD GWAS data and multi-omics quantitative trait loci (QTL), including expression QTLs (eQTLs), protein QTLs (pQTLs), splicing QTLs (sQTLs), and m6A-QTLs (mQTLs). Additionally, machine learning models were applied to validate the causal association between RNA methylation dysfunction and AMD using Bulk RNA sequencing data from 31 normal donors and 37 AMD patients. RESULTS: The single-cell transcriptome data analysis revealed massive dysregulation of RNA methylation-related gene expression in the RPE of AMD patients. SMR revealed causal associations between key RNA methylation regulators (METTL3, NSUN6, and MRM1, etc.) and AMD onset. Machine learning models further validated these findings and demonstrated a high accuracy of AMD risk prediction by using the above-identified RNA methylation-related genes: METTL3, NSUN6, and MRM1. Furthermore, METTL3 and NSUN6 were found to have a protective effect, while MRM1 was associated with an increased risk of AMD. CONCLUSION: The results reveal the implication of dysregulation of RNA methylation-related gene expression in the RPE of AMD patients and further demonstrated a causal association between RNA methylation-related genes (METTL3, NSUN6, and MRM1) and AMD. These findings highlight the importance of RNA methylation in the pathogenesis of AMD and offer potential biomarkers and therapeutic targets for AMD management.