Thalassemia intermedia encompasses a number of clinical conditions ranging in severity from beta-thalassemia carrier state to transfusion-dependent thalassemia major. The molecular bases of thalassemia intermedia, only partially defined, are very heterogeneous, but in general any factor able to reduce the globin-chain imbalance results in a milder form of thalassemia. These factors are the presence of a silent or mild beta-thalassemia allele, associated with a high residual beta-globin production, and the coinheritance of alpha-thalassemia or of genetic determinants that increase the gamma-chain production. Less frequent mechanisms are double heterozygosity for beta-thalassemia and triplicated alpha genes, and the presence of a hyperunstable hemoglobin variant. However, for a consistent number of beta zero-thalassemia homozygotes with a thalassemia intermedia phenotype the modifying factor has not been defined yet. In contrast, there are simple beta-thalassemia carriers who, for unknown reasons, have an unusually severe clinical phenotype.