Kaposi sarcoma-associated herpesvirus (KSHV) is endemic in sub-Saharan Africa. Infection in childhood involves mother-to-child transmission and transmission between siblings or other close contacts. Large amounts of viral DNA in saliva have been linked to transmission from mother to child. To investigate factors contributing to the shedding of KSHV in the saliva of mothers in rural South Africa, we sequenced the HLA-A alleles of 448 mothers and the HLA-DRB1 alleles of 363 mothers and compared their HLA types with viral loads in saliva.Viral load was quantified with real-time polymerase chain reaction on DNA extracted from saliva. HLA-A and HLA-DRB1 allele groups were determined by sequencing-based typing.We found that 2 HLA-A alleles, A*6801 and A*4301, and 1 HLA-DRB1 allele group, DRB1*04, were associated with shedding of KSHV in saliva. KSHV could be detected more frequently in mothers carrying at least 1 copy of HLA-A*6801 or HLA-A*4301, and higher viral loads were found in HLA-A*68- and HLA-DRB1*04-carrying mothers.These findings could suggest that 2 HLA-A alleles, A*6801 and A*4301, and 1 HLA-DRB1 allele group, DRB1*04, that are more frequent in African populations might be associated with an impaired control of KSHV and, hence, increased shedding in saliva.