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The objective of this study was to determine the effectiveness of trivalent inactivated influenza vaccine (TIV) for the prevention of laboratory-confirmed influenza and influenza-like illnesses (ILI) among children and adolescents receiving therapy for acute leukemia.A retrospective review of the demographic and clinical characteristics of 498 patients at a pediatric cancer center who received therapy for acute leukemia during 3 successive influenza seasons (2010–2011 through 2012–2013).In 498 patient seasons with a known immunization history (median age, 6 years; range, 1–21), 354 patients (71.1%) were immunized with TIV and 98 (19.7%) received a booster dose of vaccine. Vaccinated and unvaccinated patients had generally similar demographic characteristics. There were no differences in the overall rates of influenza or ILI between vaccinated and unvaccinated patients overall, or in any individual season. There was no difference in the rates of influenza or ILI between patients who received 1 dose of vaccine and those who received 2 doses. Time to first influenza infection and time to first ILI in vaccinated and unvaccinated patients were not different.TIV did not protect children and adolescents with acute leukemia against laboratory-confirmed influenza or ILI. Future prospective studies should assess TIV effectiveness in high-risk subpopulations and alternative strategies to prevent influenza should be considered in this population.