TLR2 and TLR4 genetic variation has been investigated among the Saudis with the aim of gaining further insight into the evolutionary history of the Arabian Peninsula. Two polymorphisms located in the TLR2 gene (Pro631His and Arg753Gln, rs5743704 and rs5743708, respectively), and two (Asp299Gly and Thr399Ile, rs4986790 and rs4986791, respectively), located in the TLR4 gene have been genotyped in 201 unrelated indi-viduals from Saudi Arabia. While the G allele has been fixed in the Arg753Gln (g.2477 G > A) polymorphism, Pro631His (g.2111 C > A) show remarkable frequencies, a polymorphism that until now has been reported exclusively among European populations. The two TLR4 markers analyzed showed moderate frequencies (ranging from 4% to 5%). Considering the reported protective role of these polymorphisms against malaria, the data suggest that the regional variation at these gene loci could have been shaped by both evolutionary infection pressure and bidirectional human migrations in the past. The population admixture may be due to the existence of gene flow from Sub-Saharan Africa and the Levant to the Arabian Peninsula.