Background: Several previous studies reported that the Venezuelan Warao Indians presented unusual genetic characteristics. Aim: The present study checked previous reports of a high frequency of hereditary persistence of fetal hemoglobin (HPFH) and examined other hematological traits. Subjects and methods: Standard hematology, electrophoresis on cellulose acetate, fetal hemoglobin alkali denaturation, -globin chain, DNA amplification and sequencing, and denaturing gradient gel electrophoresis determinations were performed in 269 individuals living in two localities of the Orinoco River Delta. Results: Two s genes, in apparently non-related individuals, were found. HPFH, detected in this same population of Warao Indians 25 years ago, was present in heterozygous form in five individuals from a large kindred, with hemoglobin F levels ranging from 3.7% to 8%, and with a pancellular distribution. The HPFH mutation was of the deletional type. -globin gene haplotypes were determined by direct counting (through family studies) in 150 chromosomes; 26% of the 150 examined cluster presented haplotype 2, 22% haplotype 6, and 13% a new, Warao haplotype. Haplotype 3, of probable African origin, was also found with a frequency of 5%. Conclusions: The presence of the HPFH mutation was confirmed, and the new -globin gene haplotype together with the presence of other rare variants indicates that the Warao are very distinctive in relation to other Native Americans. Evidence was also found of a slight admixture from Africa-derived subjects (Layrisse et al. 1988).FONACIT S1-200200539, G-2005000373, CODECIH-UC 2005-011 and FONACIT-ECOS-NORD, No. PI 2005000758.