Over 325 million people worldwide are living with hepatitis B and C viral infections and are at greater risk of developing hepatocellular carcinoma. The interactions between killer cell immunoglobulin-like receptors (KIRs) and their cognate ligands, human leukocyte antigens, modulate both infection processes and disease progression. We report here (1) genotype and haplotype variations in
KIR
genes in Cameroon and (2) their impact on susceptibility to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In 98 unrelated individuals (33 HCV+, 31 HBV+, and 34 uninfected healthy controls), we determined the presence of 15
KIR
genes by polymerase chain reaction–sequence-specific primer techniques. One pseudogene and all 14
KIR
genes were present. We identified 36 KIR genotypes, 5 of which have not been previously reported in public databases. Two inhibitory (
KIR2DL1
and
KIR2DL3
) and three activating (
KIR2DS4
,
KIR2DS2
, and
KIR2DS3
) genes were present in all HCV-infected individuals. Similarly,
KIR3DL1
,
KIR2DL1
, and
KIR2DS4
were present at 100% in the HBV+ group. Compared with uninfected healthy controls, the frequencies of
KIR2DL2
and
KIR3DS1
were significantly lower in the HBV+ group (
p
= 0.003 and
p
< 0.001, respectively). Conversely,
KIR3DS1
was significantly overrepresented in the HCV+ group compared with controls (97.0% vs. 64.7%, respectively,
p
< 0.001). These results may imply that
KIR3DS1
carriers were less likely to be HBV infected, but may be predisposed to HCV infection compared with uninfected controls, indicating their important role in transmission of these viruses. However, phenotypic, functional, and genomic studies to elucidate the role of these KIR genotypes and haplotypes in infection with HBV and HCV are important.