Background: Hereditary red cell disorders are associated with a protective effect against malaria, which results in an increased prevalence in malaria-endemic areas. Migratory flows from these areas are resulting in a marked increase in such abnormalities in Southern Spain. Methods: All hemoglobin disorders diagnosed between 1997 and 2010 have been recorded. Since 2008, we have performed systematic screening for hemoglobinopathies on African patients. A high-pressure liquid chromatography system was used as screening method for structural hemoglobinopathies and for separation of hemoglobin (Hb) F and A2. Results: We detected 666 cases in patients of foreign origin and 308 in native Spanish patients. Thalassemias (thal) are the most frequent disorders amongst the local population: β-thal minor, 57.1% (176/308); α-thal, 18.2% (56/308), and δβ-thal, 7.8% (24/308). In ethnic minorities, there is a huge variety of hemoglobinopathies: heterozygous Hb S, 45% (300/666); heterozygous Hb C, 15% (100/666); β-thal minor, 13.7% (91/666); α-thal, 10.2% (68/666); Hb SS in 14 patients, and Hb CC in 9 patients. Of the native patients, 14 were found to have Hb AS and 9 Hb AC. Conclusion: Given the modern migratory flows, greater knowledge of these disorders is needed by all medical staff, and new practical and cost/time-effective diagnostic approaches have to be devised.