RATIONALE: Upper respiratory tract infection is a guideline accepted risk domain for the loss of asthma control. The ionotrophic nucleotide receptor P2X(7) regulates compartmentalized acute inflammation and the immune response to airway pathogens. OBJECTIVES: We hypothesized that variability in P2X(7) function contributes to neutrophilic airway inflammation during a cold and thereby is linked to acute asthma. METHODS: Research volunteers with asthma were enrolled at the onset of a naturally occurring cold and monitored through convalescence, assessing symptoms, lung function, and airway inflammation. P2X(7) pore activity in whole blood samples was measured using a genomically validated flow cytometric assay. MEASUREMENTS AND MAIN RESULTS: Thirty-five participants with mild to moderate allergic asthma were enrolled and 31 completed all visits. P2X(7) pore function correlated with the change in nasal lavage neutrophil counts during the cold (R(s) = 0.514, P = 0.004) and was inversely related to the change in asthma symptoms (R(s) = -0.486, P = 0.009). The change in peak expiratory flow recordings, precold use of inhaled corticosteroids, and P2X(7) pore function were multivariate predictors of asthma symptoms (P = 0.001, < 0.001 and = 0.003 respectively). Attenuated P2X(7) activity was associated with the risk of losing asthma control (crude odds ratio, 11.0; 95% confidence interval, 1.1-106.4) even after adjustment for inhaled corticosteroids and rhinovirus (odds ratio, 15.0). CONCLUSIONS: A whole blood P2X(7) pore assay robustly identifies participants with loss-of-function genotypes. Using this assay as an epidemiologic tool, attenuated P2X(7) pore activity may be a novel biomarker of virus-induced loss of asthma control.