Background: A variety of illnesses, including acute and chronic hepatitis, as well as asymptomatic HBV carriers, can result from HBV infection. The host immune system's variability may contribute to the different ways that HBV infection manifests clinically. By regulating HBV replication, cytokines (such as IL-10 and IL-28B) are crucial in reducing acute HBV infection and assisting in the recovery of HBV in many models. Objectives: In this research we aimed to ascertain how IL-10 and IL-28B genetic polymorphism affect the progression of hepatitis B virus infection. Methodology: During the period from August 2023 to February 2024, blood samples were collected from 131 individuals, aged between (6-76) years, and they were divided into two groups, the control group (40) that were collected from healthy people and the patient group (91) samples collected from people infected with HBV. The study groups were divided according to age, sex and residency. The level of interleukins IL-10 and IL-28B in serum was assessed immunologically using ELISA technology in the control and patient groups, and their relationship with hepatitis B infection was determined. Results: The current study revealed that the infection rate in the age groups (21-40) and (50≥) was higher than (20≤) and (41-50), males more than females, and in urban residents more than rural residents, and there was a statistically significant difference between those groups compared with the control group. The Mean ± SE of interleukin-10 in the patient group was higher than in control group with P-value <0.0001, as the current study demonstrated an increase in the level of interleukin-10 when infected with hepatitis B, while the level of IL-28B decreases when infected with hepatitis B, the Mean ± SE in patient group was lower than in control group. Conclusion: After DNA sequence analysis to detect genetic polymorphism in IL-10 & IL-28B, it was found that A/A genotype has the highest frequency in IL-10 gene rs1800896 in the patient group, and in the control group it was A/G genotype, while in IL-28B gene rs8099917, T/T genotype was the highest frequency in both groups.