The effort to vaccinate the US population against the 2009 H1N1 influenza virus hinged, in part, on public confidence in vaccine safety. Early in the vaccine program, >20% of parents reported that they would not vaccinate their children. Concerns about the safety of the vaccines were reported by many parents as a factor that contributed to their intention to forgo vaccination (see www.hsph.harvard.edu/news/press-releases/2009-releases/survey-40-adults-absolutely-certain-h1n1-vaccine.html and www.med.umich.edu/mott/npch/reports/h1n1.htm). The safety profiles of 2009 H1N1 monovalent influenza vaccines were anticipated to be (and have been) similar to those of seasonal influenza vaccines, for which an excellent safety profile has been demonstrated. Here we describe steps taken by the US government to (1) assess the key federal systems in place before 2009 for monitoring the safety of vaccines and (2) integrate and upgrade those systems for optimal vaccine-safety monitoring during the 2009 H1N1 monovalent influenza vaccination program. These efforts improved monitoring of 2009 H1N1 vaccine safety, hold promise for enhancing future national monitoring of vaccine safety, and may ultimately help improve public confidence in vaccines.