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Researchers have proposed a possible correlation between age-related macular degeneration (AMD) and inflammation or C-reactive protein (CRP) levels. We investigated the potential causal relationship between CRP levels and AMD. Single-nucleotide polymorphisms (SNPs) associated with CRP exposure were selected as the instrumental variables (IVs) with significance (<i>p</i> < 5 × 10⁻⁸) from the genome-wide association study (GWAS) meta-analysis data of Biobank Japan and the UK Biobank. GWAS data for AMD were obtained from 11 International AMD Genomics Consortium studies. An evaluation of causal estimates, utilizing the inverse-variance-weighted (IVW), weighted-median, MR-Egger, MR-Pleiotropy-Residual-Sum, and Outlier tests, was conducted in a two-sample Mendelian randomization (MR) study. We observed significant causal associations between CRP levels and AMD (odds ratio [OR] = 1.13, 95% CI = [1.02–1.24], and <i>p</i> = 0.014 in IVW; OR = 1.18, 95% CI = [1.00–1.38], and <i>p</i> = 0.044 in weight median; OR = 1.31, 95% CI = [1.13–1.52], and <i>p</i> < 0.001 in MR–Egger). The causal relationship between CRP and AMD warrants further research to address the significance of inflammation as a risk factor for AMD.