A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) β-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia Intermedia phenotype associated with the different combinations of alleles. The presence or absence of the favorable alleles could accurately predict the type of thalassemia in 83.2% of the cases. The percentage of correct predictions made from the β-thalassemia mutations and the XmnI SNP alone were significantly improved by the adjustment with the 3 other modifiers; from 73.6% to 83.2% (P<0.001). In this study, we showed that predictions based on genetic modifiers can foresee the Major or Intermedia type of β-thalassemia, even in cohorts of patients with various β-globin genotypes.