Background: AA+/--thalassemia is known to be prevalent in the Eastern region of Saudi Arabia. There are no large scale reports regarding the effect of alpha-thalassemia on red cell indices of cord blood from Saudi Arabia. Similarly, there are no reports regarding the interaction of AA+/--thalassemia and the sickle cell gene in relation to red cell indices in cord blood. To address these issues, we undertook a study on neonatal cord blood samples., Materials and Methods: In a prospective study, cord blood samples from 504 neonates from the Qatif area of the Eastern Province of Saudi Arabia were analyzed for complete blood counts (CBC) and cellulose acetate Hb electrophoresis. Hb S was confirmed by citrate agar Hb electrophoresis., Results: There were 243 case samples with normal Hb electrophoresis (Hb A 27.2+/-7% and Hb F 72.6+/-7.7%). Their mean Hb (g/dL), RBC (x10(12) /L), Hct (%), MCV (fl), MCH (pg), MCHC (g/dL), RDW-SD (fl) and RDWCV (%) were 15.05+/-1.6, 4.5+/-0.5, 47.4+/-5.3, 106+/-8, 33.6+/-2.3, 31.8+/-1.7, 69.2+/-9.5 and 17.9+/-1.7, respectively. There were 136 cases with alpha-thalassemia trait (alphaTT), 57 cases with sickle cell trait (SCT) and 50 cases of sickle cell trait with alpha-thalassemia trait (SCT/alphaTT). There were 10 cases of Hb H disease (6 definite), including one with sickle cell disease (SCD) and two with SCT, Hb Bart's 23.9%-43.6%; four probable with Hb Bart's 10.9%-16.1%, and one with SCT. The effect on red cell parameters in Hb H disease were most pronounced. In addition, there were seven cases of SCD, four of whom had coexistent AA+/--thalassemia trait (SCD/alphaTT)., Conclusion: The prevalence of alpha-thalassemia in this cohort of Saudi population was 39.99%. Hb H disease appeared as common as SCD. Sickle cell gene was seen in 23.4% of neonatal samples. alpha-Thalassemia gene significantly reduces MCH, MCV, RDW-SD, Hct, Hb, and increases RBC count in both normal or sickle cell trait neonates. Generally, the variation of red cell parameters is directly proportional to the amount of Hb Bart's in the cord blood. Sickle cell gene in itself produces low MCV, RDW-SD and MCH in cord blood. Further, normal reference values for red cell parameters of cord blood are established.