XPF and ERCC1 exist as a heterodimer to be stable and active in cells and catalyze DNA cleavage on the 5’-side of a lesion during nucleotide excision repair. Both XPF and ERCC1 are unstable in mammalian cells when they exist on their own, in the absence of the other partner. To characterize the specific interaction between XPF and ERCC1, we expressed the human ERCC1 Binding domain of XPF (XPF-EB) and the XPF Binding domain of ERCC1 (ERCC1-FB) in Escherichia coli. ERCC1-FB was expressed in inclusion bodies and had to be refolded in the presence of XPF-EB; ERCC1-FB aggregated if XPF-EB was not present in the refolding. Milligram quantities of a heterodimer were characterized with gel filtration chromatography, a Ni-NTA binding assay, and analytical ultracentrifugation. Cross-linking experiments at high salt concentrations revealed that XPF interacts with ERCC1 mainly through hydrophobic interactions. XPF-EB was also shown to homodimerize in the absence of ERCC1. NMR data for the complex showed evidence of proper folding. NMR cross-saturation methods were applied to map the residues involved in formation of the XPF-EB / XPF-EB homodimer and the XPF-EB / ERCC1-FB heterodimer. Helix H3 and the C-terminal region of XPF-EB were either within or in close proximity to the homodimer interface, while the ERCC1-FB binding site of XPF-EB was distributed across helix H1, a small part of H2, H3, and the C-terminal region, most of which exhibited large changes in chemical shift upon ERCC1 binding. The XPF-EB heterodimeric interface is larger than the XPF-EB homodimeric one, which could explain why XPF has a stronger affinity for ERCC1 than for a second molecule of XPF. The XPF binding sites of ERCC1 were located in helices H1 and H3, and in the C-terminal region, similar to the involved surface of XPF. We used cross-saturation data and the crystal structure of related proteins to model the two complexes.