HbE [beta 26 Glu-Lys] is the second most common abnormal Hb in humans. HbE when associated with beta thalassemia (HbE/beta thalassemia) in compound heterozygous state results in a clinically severe condition. HbE/beta thalassemia has a very variable clinical phenotype. One of the possible explanations for the observed variable clinical severity is variation of alpha gene number. The main aims of this study were to determine the frequency of alpha deletion/mutations and triplication in HbE/beta thalassemia patients and to study the effect of alpha gene numbers on the phenotype of these patients. 240 HbE/beta thalassemia patients who attended the Hematology Outpatient Department of the Institute were studied. Patients were divided into three groups mild (score=0-3.5), moderate (score=4-7) and severe (score=7.5-10). alpha deletion was found in 22 (7.5%), out of these 22 patients 16 (11 alphaalpha/-alpha(3.7), 4-alpha(3.7)/-alpha(3.7) & 1 alphaalpha/--(SA)) were from Gp I and 6 (alphaalpha/-alpha(3.7)) were from Gp II. alpha triplication was found in 7 (2.9%) and out of these 7 patients 5 were (alphaalpha/alphaalphaalpha(anti-3.7)) from Gp III and 2 were (alphaalpha/alphaalphaalpha(anti-3.7)) from Gp II. The most common interaction was found to be HbE/beta thalassemia and deletional alpha(+)-thalassemia (alphaalpha/-alpha(3.7)) followed by others. alpha deletions and point mutations genotype were mostly observed in the individuals from Gp I while alpha triplication was most frequent in Gp III individuals. Interaction of HbE/beta thal with alpha-thalassemia is common in the Indian population. Patients inheriting alpha deletions and point mutations behaved mildly with some exceptions, while patients with alpha triplication had a severe phenotype requiring frequent transfusions.