Ubiquitination is an important post-translational modification that controls nearly every facet of a cell’s life and death. Only ubiquitin ligases E3 can specifically recognize substrates during ubiquitination, so E3 plays a pivotal role in ubiquitination and degradation of substrate proteins. Human apoptosis-resistant E3 ubiquitin protein Ligase 1 (AREL1) belongs to the Homology to E6AP C-Terminus(HECT) ubiquitin ligase family, and it inhibits apoptosis through ubiquitinating mitochondrial proapoptotic proteins such as SMAC, HtrA2, and ARTS, which are degraded by the 26 S proteasome. Here, the crystal structure of the HECT domain of AREL1 (AREL1^HECT) at 3.2 ? resolution is reported, and structural comparisons of AREL1^HECT against different HECT E3 ligases are conducted. Size Exclusion Chromatography (SEC) and Small Angle X-ray Scattering (SAXS) indicate that there are diverse oligomeric states of AREL1^HECT in solution, and the SAXS 3D model further suggests that AREL1^HECT can dimerize in solution. These findings offer a structural basis for studying the complex of AREL1^HECT and ubiquitin, and provide insights into molecular mechanisms of substrate ubiquitination by AREL1.