Hemoglobin H (Hb H) disease is the most severe non-fatal form of a-thalassemia syndrome. In general, most patients with Hb H rarely require blood transfusion, splenectomy or even standard iron chelation therapy. However, there is increasing evidence that Hb H disease might not be as benign, and patients with variations in clinical severity are increasingly observed, especially among those with non-deletional Hb H disease. The clinical course of non-deletional Hb H disease appears to be remarkably variable, even among patients who have identical genotypes. This suggests that other factors play a role in modifying the degree of clinical severity. This study aimed to investigate determining factors for disease severity in patients with Hb H disease including liver enzymes, total and directed bilirubin, serum ferritin and complement C3 level. This study was conducted on 44 patients with Hb H disease from Sunpasitthiprasong hospital, Ubon Ratchathani, Thailand. From scoring criteria in this study, Hb H patients were categorized into 3 groups of severity: 17 patients (39%) were mild, 21 patients (48%) were moderate, and 6 patients (13%) were severe phenotype. The results of this study demonstrated that factors that significantly correlated with severity and were considerably recommended to use for distinguishing mild from severe Hb H patients were aspartate aminotransferase (AST) and ferritin level. Parameters that might influence severity of Hb H disease included alanine phosphatase (ALP), complement C3 level, total bilirubin, direct bilirubin and indirect bilirubin, which needs further study for clearly understanding. The wealth of information in this study may provide insight regarding the prediction of clinical courses and could help to formulate proper management for these patients.