Staphylococcus aureus produces compounds that interfere with complement deposition. We hypothesized that humans have developed countermeasures to staphylococcal complement evasion and we screened for single nucleotide polymorphisms in the serine protease C1 inhibitor (C1INH) gene at amino acid position 480 (valine vs. methionine) and nasal carriage of S. aureus. In our study cohort, 38 individuals were persistently colonized by S. aureus, whereas 50 were invariably culture-negative. A trend was observed towards an increased prevalence of the Val/Val genotype in noncarriers compared to persistent carriers (OR 0.50, P=0.07). The Val/Val genotype was significantly overrepresented in noncarriers compared to 463 Caucasian blood donors (OR 0.52, P=0.02). These findings suggest that susceptibility to S. aureus nasal carriage is associated with the C1INH V480M polymorphism.