The recent impact of influenza on the working-age population of the US has led to changes in the recommendations for vaccination against seasonal influenza; however, the implications of vaccinating such a population have been debated. A review of cost-effectiveness analyses of vaccinating the working-age population of the US against seasonal influenza was conducted using articles published between January 1990 and January 2010. Studies considered for inclusion were identified using MEDLINE, EMBASE and Econlit. Reviewers worked in pairs, and each team member independently extracted relevant data using a standard abstraction form. The source and appropriateness of parameters (epidemiological data, probabilities and costs), the designs employed and the sufficiency of sensitivity analysis were considered during review. Key inputs extracted from the selected studies included influenza or influenza-like illness attack rates, outpatient visits averted, total vaccination days and lost workdays. Seven studies were identified as appropriate for this review. All studies were conducted in the US and from the societal perspective; three were randomized controlled trials and the remaining four were economic simulation models comparing vaccination and influenza antiviral drugs or no intervention; analyses focused on healthy working-age adults aged 18-49 years. Results ranged from net savings of $US68.96 to net costs of $US85.92 per person vaccinated (four studies) and net costs of $US104-1005 per episode of influenza averted (one study). Only two studies reported cost-effectiveness ratios; these ranged from $US26,565 to $US50,512 per quality-adjusted life-year gained. Nearly all of the studies conducted sensitivity analysis; results were most sensitive to variation in wage rates, levels of worker productivity, the costs and effectiveness of vaccination, and the rate of influenza illness. Review of the included studies suggests that seasonal influenza vaccination of healthy, working-age adults is generally not cost saving, requiring an investment to generate health benefits. The decision to vaccinate such a group will depend upon the societal and payer valuation of those benefits.