α-Thalassemia (α-thal), a genetic disease characterized by microcytosis, hypochromia and anemia, is predominantly caused by deletions of the α-globin genes, HBA2 and HBA1. In this study, we describe a novel 31.1 kb α-thal deletion, – –MEX3 (NC_000016.10: g.151479_182582del), observed in a Mexican family, probably originated from non homologous recombination between two Alu sequences; the 5′ Alu element has been involved in at least two other α-thal deletions [– –FIL (NG_000006.1: g.11684_43534del) and – –KOL] and possesses a core homologous sequence next to the – –MEX3 breakpoint. In addition, a 286 bp insertion in an Alu sequence downstream to the – –MEX3 3′ breakpoint was found in the studied family, – –FIL carriers, and healthy subjects, suggesting a common genetic variation in the Mexican population. We highlight the involvement of Alu elements and their core sequence in the origin of deletions in the α-globin gene cluster, and the importance of characterizing rare mutations, to better understand DNA rearrangement origins.