We determined the response of 48 Down syndrome children to 2 doses of influenza A/H1N1 vaccination. Ninety-two percent of the children reached the previously defined protective level (hemagglutination-inhibition titer ≥1:40), but only 27% of the children reached the level of ≥1:110 which was recently described to predict the conventional 50% clinical protection rate in children. Further studies, and potentially adaptations of the schedule, are needed.