Double heterozygosity for hemoglobin (Hb) E and S, known as HbSE disease, is a rare, clinically benign condition involving mild hemolysis. Only 25 cases have been reported to date. The current literature generally associates HbSE with a benign clinical course, although vaso-occlusive complications have been reported. Although only single case reports were previously available, we have observed 20 cases of HbSE and wish to report them. We examined the records of patients presenting to our hemoglobinopathy center in 2001-2013. High performance liquid chromatography (HPLC) was used for hematological assessment of blood samples with ethylenediaminetetraacetic acid. Eight patients were male and 12 female. Mean hemoglobin electrophoresis values were Hb Al: 6.3%, Hb E 34.5%, HbS: 59.5% and Hb F: 1.9%. Three patients (15%) were symptomatic with vaso-occlusive crisis and one had cerebral stroke. These were siblings. The patient with cerebral stroke was using hydroxyurea. The incidence of HbSE disease is rising due to population admixtures and racial intermarriages. Increased numbers of cases of HbSE have been detected after premarital hemoglobinopathy screening in the Antakya and Cukurova regions of Turkey. The aim of this study was to report large numbers of patients with HbSE diagnosed through the routine HPLC method. The secondary aim was to emphasize that severe vaso-occlusive crisis such as infarction symptoms could be seen in HbSE.