Abstract: Background and Objective: Interleukin-10 (IL-10) and interleukin-18 (IL-18) are important immune regulators that may have a role in HBV infection outcome. Gene polymorphisms of these cytokines can affect their expression and serum level and may be associated with liver disease severity in patients with viral hepatitis. This study aimed to investigate the polymorphisms of IL-10 and IL-18 and to explore whether such polymorphisms are associated with the natural course of HBV infection in Saudi population. Materials and Methods: The study included 327 Saudi patients with different HBV clinical outcomes. Single Nucleotide Polymorphisms (SNPs) were detected by restriction fragment length polymorphism after polymerase chain reaction (PCR-RFLP) for both IL-10 (1082G/A and 592A/C) and IL-18 (607C/A and137G/C). Results: The IL-10-1082GG genotype among cirrhotics was significantly lower than controls ((3.7 and 12.7%, respectively). While, IL-10-592AA genotype was significantly less prevalent among cirrhotics (6.4%) compared to recovered and control groups. IL-18 (607C>A) SNP analysis showed no significant difference between the studied groups. The IL-18-137CC genotype was less prevalent among cirrhotic patients (1.8%) compared to recovered group (9.7%). Also, GG genotype was statistically more prevalent among HBV cirrhotics. The polymorphisms of the promoter region of IL-10 and IL-18 genes are closely associated with susceptibility to chronic active hepatitis B and development of hepatic cirrhosis. Conclusion: The patients with AA at position IL-10-592AA may be protected against HBV infection. Moreover, CC genotype at position IL-18-137CC may be closely linked to HBV-DNA recovery.