Fpg (MutM) is a bacterial base excision repair enzyme that removes the mutagenic and/or replication-block lesions 8-oxoguanine (8-oxodG) and imidazole-ring opened purines (Fapy-derivatives) from DNA. This work shows that Fpg and its eukaryote homologue Ogg1 recognize with high affinity FapydG and bulky N7-benzyl-FapydG (Bz-FapydG). The comparative crystal structure analysis of stable complexes between Fpg and DNA duplex containing either carbocyclic cFapydG or Bz-cFapydG nucleoside provides the molecular bases of the ability of Fpg to bind both lesions with the same affinity. Both lesions are stabilized in an extrahelical anti glycosyl configuration inside the substrate binding pocket of the enzyme. To solve the steric hindrance of the benzyl group, Fpg selects the adequate rotamer of the Bz-cFapydG formamido group, allowing the expelling of the bulky group outside the binding pocket. Contrary to the binding mode of cFapydG, the particular recognition of Bz-cFapydG leads the enzyme in an unproductive complex. This work provides new structural and/or functional insights into Fpg substrate specificity and catalysis and has significant biological implications concerning the repair of bulky-Fapy-DNA adducts in vivo.