Background: Sickle cell anemia (SCA), the most common type of sickle cell disease (SCD), is associated with reduced morbidity and mortality in individuals with high fetal hemoglobin (HbF) levels. Variation in HbF levels is linked to genetic polymorphisms that influence its production. This study evaluated the frequency of the HBG2 rs7482144 polymorphism and its association with HbF levels and disease severity in patients with SCA in Odisha. Methods: This observational, cross-sectional study was conducted at the Department of Medicine, Srirama Chandra Bhanja Medical College and Hospital, Cuttack, from August 2023 to August 2024. Patients with homozygous SCD, confirmed through Hb electrophoresis and in steady state, were included. Disease severity was classified according to van den Tweel et al. Deoxyribonucleic acid (DNA) was extracted using theZybio Nucleic Acid Extraction Kit. Genotyping of the HBG2 rs7482144 polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism. Results: A total of 94 patients were included. The mean (SD) age of the patients was 29.79 (9.90) years. The average number of hospitalizations was 12.79 (9.15), and the mean number of blood transfusions was 8.67 (8.86). The mean (SD) HbF level was significantly higher in patients with the HBG2 rs7482144 TT genotype [20.82 (3.16) %] compared to those with the CT [18.99 (4.82) %] and CC genotypes [16.18 (4.57) %] (P<0.001).The TT genotype (71.1%) was significantly higher in patients with mild SCA (P=0.018). Conclusion: The T allele of the HBG2 rs7482144 polymorphism was associated with higher HbF levels, and the TT genotype did not correlate with increased disease severity.