OBJECTIVES: To estimate the impact of vaccination timing on the cost-effectiveness of seasonal influenza vaccination in pregnancy for prevention of disease in women and infants under 6 months of age. METHODS: We constructed an open cohort Markov simulation of US pregnant women and infants under 6 months of age for 1 calendar year, from July 1 through June 30.  National statistics on live births and infant mortality were used to generate probabilities of delivery and infant death based on gestational age.  Each week, women entered the cohort with new pregnancies, and left by delivery; infants entered by delivery and left by death or reaching 6 months of age.  Annual influenza-attributable rates of outpatient visits and hospitalizations for pregnant women and infants were obtained from the literature, and adjusted to weekly incidences using CDC data on influenza-positive respiratory isolates.    In the base case, we assumed vaccination would begin in calendar week 40, be administered at routine prenatal visits across all gestational ages, and continue throughout the rest of the year, with  vaccine efficacy of 73% for prevention of maternal flu and 63% for prevention of flu in infants under 6 months.  Costs and maternal utilities were obtained from previously published analyses; we used published parental utilities for relevant infant health states.   RESULTS: Base case cost-effectiveness was $65,112/QALY gained.  Fifty-six percent of the reduction in morbidity was attributable to prevention of disease in infants, and all of this benefit was accrued by vaccination within the first 4 weeks of vaccine availability.   CONCLUSIONS: Vaccination of pregnant women against seasonal influenza is cost-effective, with much of the benefit derived from prevention of infant disease.  Vaccination is most efficient when the majority of pregnant women are vaccinated within 4 weeks of vaccine availability.