TAX1BP1 is a pleiotropic multi-domain protein involved in many important biological processes such as signal transduction, cell growth and apoptosis, transcriptional coactivation, membrane trafficking, neurotransmission and autophagy. The N-terminus of TAX1BP1 contains a SKICH domain implicated in autophagy. SKICH domains are also present in four other proteins including NDP52, CALCOCO1, SKIP and PIPP. The SKICH domains of SKIP and PIPP mediate plasma membrane localization. The functions of the SKICH domains of NDP52 and CALCOCO1 are not known. We solved the crystal structure of the TAX1BP1 SKICH domain, which has an Ig-like fold similar to the NDP52 SKICH domain. Extensive pairwise and clustered aromatic π-stacking interactions are present in the TAX1BP1 SKICH domain. The aromatic residues mediating these interactions can be classified into four groups with varying degrees of conservation among different protein families. The interactions mediated by highly conserved residues are found in the interior and one outward face of the Ig-like β-barrel, representing common structural features of the SKICH domains. Three TAX1BP1-specific pairwise interactions locate in the loop regions, each augmented by a proline-aromatic interaction. The three proline-aromatic clusters are linked together by more generic hydrophobic interactions, forming a unique hydrophobic surface at one end of the TAX1BP1 SKICH domain. The structures and homologous models of SKICH domains from different proteins reveal substantial differences in electrostatic surface properties of the domains. Together with existing biochemical data, results from the structural study suggest that an intact SKICH domain is required for the autophagy function of TAX1BP1.