We compared prevalence of hospitalization, endotracheal intubation, and death among case-patients with and without Down syndrome during pandemic (H1N1) 2009 in Mexico. Likelihoods of hospitalization, intubation, and death were 16-fold, 8-fold, and 335-fold greater, respectively, for patients with Down syndrome. Vaccination and early antiviral drug treatment are recommended during such epidemics.