West Nile virus (WNV) causes disease in ∼20% of infected humans. We previously reported that homozygosity for CCR5Δ32, a nonfunctional variant of chemokine receptor CCR5, is markedly increased among symptomatic WNV-seropositive patients from Arizona and Colorado. To confirm this, we analyzed cohorts from California and Illinois. An increase in CCR5-deficient subjects was found in both (for California, odds ratio [OR], 4.2 [95% confidence interval {CI}, 1.5–11.9] [P = .004]; for Illinois, OR, 3.1 [95% CI, 0.9 –11.2] [P = .06]). A meta-analysis of all 4 cohorts showed an OR of 4.2 (95% CI, 2.1– 8.3 [P<.0001]). Thus, CCR5 deficiency is a strong and consistent risk factor for symptomatic WNV-infection in the United States.