BackgroundSchool-located vaccination against influenza (SLV-I) has the potential to improve current suboptimal influenza immunization coverage for U.S. school-aged children. However, little is known about SLV-I's cost-effectiveness. The objective of this study is to establish the cost-effectiveness of SLV-I based on a two-year community-based randomized controlled trial (Year 1: 2009-2010 vaccination season, an unusual H1N1 pandemic influenza season, and Year 2: 2010-2011, a more typical influenza season).MethodsWe performed a cost-effectiveness analysis on a two-year randomized controlled trial of a Western New York SLV-I program. SLV-I clinics were offered in 21 intervention elementary schools (Year 1 n = 9,027; Year 2 n = 9,145 children) with standard-of-care (no SLV-I) in control schools (Year 1 n = 4,534 (10 schools); Year 2 n = 4,796 children (11 schools)). We estimated the cost-per-vaccinated child, by dividing the incremental cost of the intervention by the incremental effectiveness (i.e., the number of additionally vaccinated students in intervention schools compared to control schools).ResultsIn Years 1 and 2, respectively, the effectiveness measure (proportion of children vaccinated) was 11.2 and 12.0 percentage points higher in intervention (40.7 % and 40.4 %) than control schools. In year 2, the cost-per-vaccinated child excluding vaccine purchase (59.88in2010US) consisted of three component costs: (A) the school costs (8.25);(B)theprojectcoordinationcosts(32.33); and (C) the vendor costs excluding vaccine purchase (16.68),summedthroughMonteCarlosimulation.ComparedtoYear1,thetwocomponentcosts(A)and(C)decreased,whilethecomponentcost(B)increasedinYear2.Thecost−per−vaccinatedchild,excludingvaccinepurchase,was59.73 (Year 1) and 59.88(Year2,statisticallyindistinguishablefromYear1),higherthanthepublishedcostofprovidinginfluenzavaccinationinmedicalpractices(39.54). However, taking indirect costs (e.g., averted parental costs to visit medical practices) into account, vaccination was less costly in SLV-I (23.96inYear1,24.07 in Year 2) than in medical practices.ConclusionsOur two-year trial's findings reinforced the evidence to support SLV-I as a potentially favorable system to increase childhood influenza vaccination rates in a cost-efficient way. Increased efficiencies in SLV-I are needed for a sustainable and scalable SLV-I program