BACKGROUND: Blood collected in the United States and Canada is screened for West Nile virus (WNV) using nucleic acid testing (NAT). The role that donor-reported symptoms of infection disclosed at or shortly after donation may play in enhancing blood safety has been debated. Little data are available on subsequent manifestations of WNV-specific disease outcomes in viremic donors. STUDY DESIGN AND METHODS: Donors with initially reactive NAT results were informed by telephone and asked to complete symptom interviews. The questionnaires are focused on three time periods: the week before, the day of, and the 2 weeks after donation. Symptoms and risk factors were compared between confirmed-positive and false-positive donors (classified based on confirmatory NAT and serology). Additional analyses comparing confirmed-positive symptomatic and asymptomatic donors were conducted. RESULTS: A total of 423 of 536 initially reactive donors were interviewed between 2003 and 2006: 292 confirmed-positive for WNV and 131 false-positive. Individual symptoms were not significant predictors of WNV infection, except skin rash in the week before donation (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.2-7.9) and body aches in the period after donation (OR, 2.8; 95% CI, 1.1-7.4). Specific combinations of symptoms were not good predictors of infection, but donors with three or more concurrent symptoms before donation were more likely to have WNV infection (OR, 2.5; 95% CI, 1.2-5.1). Demographic characteristics, predonation symptoms, and serology profiles in confirmed-positive donors did not predict postdonation symptom severity. Thirty-five confirmed-positive donors (12%) sought medical care for WNV infection, with two hospitalizations, but no cases of neuroinvasive disease. CONCLUSION: The number rather than type of symptoms is associated with confirmed WNV infection, but the overall predictive value is low. Very few infected donors develop clinically significant disease.