Significance Tripartite motif or TRIM proteins make up the largest superfamily of RING-domain E3 ubiquitin ligases. These enzymes function in a wide variety of important cellular processes, particularly innate antiviral response mechanisms. Dimerization is critical for the function of many TRIM proteins. Here we show how TRIM25 dimerizes and demonstrate that this dimerization mode is apparently conserved across the entire TRIM protein family. Our results reveal how the dimerization domain positions the other TRIM effector domains to recognize and ubiquitylate substrates and how the TRIM5 family can form higher-order hexagonal assemblies that increase the avidity of substrate recognition.