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Introduction: Detection of β-thalassemia trait or carriers (β-TT) depends significantly on an increase in Hemoglobin A 2 (HbA 2 ) levels, which is found at low levels (<3%) in normal healthy individuals and elevated levels (≥3.5%) in β-TT individuals. The study was designed to evaluate the reliability of the diagnostic parameter HbA 2 in the differentiation of β-TT and non-β-TT in Saudis., Methods: The widely used high performance liquid chromatography (Variant II Bio-Rad) was used to measure HbA 2 levels in blood. Sanger sequencing was used to screen the variation in globin genes (HBB, HBD, HBA1, and HBA2). All the study subjects were divided into βTT and non-βTT (wild) categories based on the presence or absence of HBB variations and further sub-divided into false positive, true positive, false negative, and true negative, based on HbA 2 values., Results: Out of 288 samples, 96 had HBB gene mutations. Of the 96 β-TT samples, sickle cell trait (SCT) samples (n = 58) were excluded, while the remaining (38 β-TT) were included in the detailed analysis: seven subjects with the HBB mutation had normal HbA 2 (<3%), and three were borderline (3.1-3.9%). The remainder (n = 28) had an elevated HbA 2 level (>4%). Based on HbA 2 analysis alone, both these groups would be incorrectly diagnosed as normal. Similarly, of the 189 non-β-TT samples, 179 had normal HbA 2 , eight had borderline HbA 2 , and two had a HbA 2 level above 4%. Based on HbA 2 analysis alone, borderline and >4% HbA 2 individuals, negative for β-TT, can be incorrectly diagnosed as carriers., Conclusion: Given the percentage of samples falling in the HbA 2 "borderline" and "normal" categories, it can be concluded that HbA 2 has a measure of unreliability in the diagnosis of β-thalassemia carriers.