Recent evidence has reinforced the belief in immunosurveillance as a powerful mechanism against cancer development. The natural killer (NK) cell has been recognized as a potent agent of cancer immunosurveillance. A Japanese cohort study correlated natural cytotoxic activity levels with subsequent cancer development and identified NK cell lectin-like receptor K1 gene (KLRK1/NKG2D) polymorphisms as genetic markers of cancer predisposition. In the present study, we genotyped 82 reference cell lines and 388 newborn samples at 10 KLRK1 region variants by TaqMan((R)) allelic discrimination assays and showed that the same polymorphisms occur at similar frequencies in Europeans. The same haplotype block that has been associated with lower natural cytotoxic activity also occurred with the highest frequency in our sample. We further detected evidence suggestive of natural selection at some of the loci analyzed and more importantly, sex specificity of this selection. It appeared that heterozygosity at loci forming a haplotype block was unfavorable for boys. Given the relevance of NK cells in fetal survival, this finding has potential implications in the study of genetics of maternofetal recognition. Our preliminary findings are of marginal statistical significance and should be replicated in a larger sample. We believe that our results will increase awareness of the involvement of KLRK1 in cancer immunosurveillance and possibly in prenatal selection.