Common X-linked genetic polymorphisms are expected to alter cellular responses affecting males and females differently through sex-linked inheritance pattern as well as X chromosome (ChrX) mosaicism and associated ChrX skewing, which is unique to females. We tested this hypothesis in ex vivo lipopolysaccharide and phorbol ester-stimulated polymorphonuclear granulocytes (PMNs) and monocytes from healthy volunteers (n = 51). Observations were analyzed after stratification by sex alone or the presence of variant IRAK1 haplotype a common X-linked polymorphism with previously demonstrated major clinical impacts. Upon cell activation, CD11b, CD45, CD66b, CD63, and CD14 expression was markedly and similarly elevated in healthy males and females. By contrast, PMN and monocyte activation measured by CD11b, CD66b, and CD63 was increased in variant-IRAK1 subjects as compared with WT. Stratification by IRAK1 genotype and sex showed similar cell activation effect on variant-IRAK1 subjects and an intermediate degree of cell activation in heterozygous mosaic females. The increased membrane expression of these proteins in variant-IRAK1 subjects was associated with similar or increased intersubject but uniformly decreased intrasubject cell response variabilities as compared with WT. We also tested white blood cell ChrX skewing in the healthy cohort as well as in a sample of female trauma patients (n = 201). ChrX inactivation ratios were similar in IRAK1 WT, variant, and heterozygous healthy subjects. Trauma patients showed a trend of blunted ChrX skewing at admission in homozygous variant-IRAK1 and heterozygous mosaic-IRAK1 female subjects as compared with WT. Trauma-induced de novo ChrX skewing was also depressed in variant-IRAK1 and mosaic-IRAK1 female trauma patients as compared with WT. Our study indicates that augmented PMN and monocyte activation in variant-IRAK1 subjects is accompanied by decreased intrasubject cellular variability and blunted de novo ChrX skewing in response to trauma. A more pronounced cell activation of PMNs and monocytes accompanied by decreased response variabilities in variant-IRAK1 subjects may be a contributing mechanism affecting the course of sepsis and trauma and may also impact sex-based outcome differences due to its X-linked inheritance pattern and high prevalence.