DNA ligase IV catalyses the final ligation step in the non-homologous end-joining (NHEJ) DNA repair pathway and requires interaction of the ligase with the Xrcc4 'genome-guardian', an essential NHEJ factor. Here we report the 3.9 A crystal structure of the Saccharomyces cerevisiae Xrcc4 ortholog ligase interacting factor 1 (Lif1p) complexed with the C-terminal BRCT domains of DNA ligase IV (Lig4p). The structure reveals a novel mode of protein recognition by a tandem BRCT repeat, and in addition provides a molecular basis for a human LIG4 syndrome clinical condition.