BACKGROUND: Nontransfusion-dependent thalassemia (NTDT) refers to a diverse group of thalassemia mutations and clinical phenotypes that do not require chronic transfusions. It is increasingly prevalent in the United States. PROCEDURE: This study reviews the epidemiology and clinical characteristics of 138 patients with NTDT treated at four US thalassemia centers from 1997 to 2014. Data on laboratory results, transfusions, and clinical complications were collected from patient charts. RESULTS: Overall, 84 patients with alpha-thalassemia (62 deletional hemoglobin H; 22 nondeletional hemoglobin H), 39 with beta-thalassemia (26 with homozygous or double heterozygous beta mutations; 13 with single beta mutations with or without alpha triplication), and 15 with E/beta-thalassemia (12 E/beta(0) ; three E/beta(+) ) were identified. At study entry, the median age for patients with alpha-thalassemia was 2.3 years; 9.2 years for patients with beta-thalassemia and 2.2 years for patients with E/beta-thalassemia. Most patients with alpha-thalassemia were Asian. Patients with beta-thalassemia were predominantly Caucasian (46%) or of African descent (36%). Twenty percent of patients were born outside the United States and 5% were transfused before immigration. Complications varied by genotype and age. Individuals with nondeletional hemoglobin H were severely affected and, despite their young age, had many complications. Iron overload increased with age and was more common in patients who received transfusions. CONCLUSIONS: NTDT in the United States is a multi-ethnic disease with different genotypic mutations and phenotypic manifestations. A higher than expected proportion of patients was Black/African American. NTDT-related complications are common and increase with age, supporting a need for early diagnosis.