Hb Plasencia is a thalassemic hemoglobin (Hb) mutation caused by a leucine to arginine replacement at residue 125 of the α2-globin chain (HBA2:c.377T>G). This variant was first described in the heterozygous state in association with a very mild α-thalassemic phenotype in three members of a Spanish family from Plasencia, Western Spain. Reviewing the molecular characterization of 308 Portuguese individual suspected of having α-thalassemia (α-thal) we found Hb Plasencia to be the second most frequent mutation after the -α(3.7) deletion.