Background: The risk of revision surgery following total joint arthroplasty (TJA) may be influenced by genetic factors. Therefore, we sought to identify genetic variants associated with the risk of revision surgery in a genomewide association study. Methods: We investigated a cohort of 1,130 twins from the Swedish Twin Registry treated with TJA. During a mean of 9.4 years of follow-up, 75 individuals underwent revision surgery for aseptic loosening (the primary outcome) and 94, for any reason (the secondary outcome). Genetic information was collected using the Illumina OmniExpress and PsychArray panels, and the Haplotype Reference Consortium served as the reference for gene imputation. Adjusted Cox regression models were fitted to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Nine single-nucleotide polymorphisms (SNPs) reached genomewide significance for aseptic loosening. The first SNP, rs77149046, located in the endosome-lysosome associated apoptosis and autophagy regulator family member 2 (ELAPOR2) gene, conferred an HR of 5.40 (CI, 3.23-9.02; p = 1.32×10⁻¹⁰), followed by 4 SNPs within the region coding for sodium-dependent taurine and beta-alanine transporter (SLC6A6), with HRs ranging from 3.35 to 3.43. The sixth SNP, rs7853989 (HR, 3.46; CI, 2.33-5.13; p = 6.91×10⁻¹⁰), was located in a region coding for the ABO blood group system. This SNP has been described as predictive for blood type B. Seven significant SNPs were found for the risk of revision for any reason, with the first 4 again being located in the SLC6A6 region. The leading SNP, rs62233562, conferred an HR of 3.11 (CI, 2.19-4.40; p = 1.74×10⁻¹⁰) for revision surgery. Similar HRs were found for SNPs 3:14506680 (p = 1.78×10⁻¹⁰), rs2289129 (p = 1.78×10⁻¹⁰), and rs17309567 (p = 3.16×10⁻¹⁰). The fifth SNP, rs11120968, was located in the calmodulin-binding transcription activator 1 (CAMTA1) gene (HR, 2.34; CI, 1.74-3.13, p = 1.45×10⁻⁸). Conclusions: We identified 12 unique SNPs associated with an increased risk of revision surgery. Among these, 2 were in ELAPOR2, which is closely linked to bone formation. Another SNP is located in a gene region encoding for the ABO system, which merits further studies of causal relationships. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.