Background: Japanese encephalitis (JE) virus is the leading vaccine-preventable cause of encephalitis in Asia. For most travelers, JE risk is very low but varies based on several factors, including travel duration, location, and activities. To aid public health officials, health care providers, and travelers evaluate the worth of administering/receiving pre-travel JE vaccinations, we estimated the numbers-needed-to-treat to prevent a case and the cost-effectiveness ratios of JE vaccination for U.S. travelers in different risk categories. Methods: We used a decision tree model to estimate cost per case averted from a societal and traveler perspective for hypothetical cohorts of vaccinated and unvaccinated travelers. Risk Category I included travelers planning to spend >= 1 month in JE-endemic areas, Risk Category II were shorter-term (<1 month) travelers spending >= 20% of their time doing outdoor activities in rural areas, and Risk Category III were all remaining travelers. We performed sensitivity analyses including examining changes in cost-effectiveness with 10- and 100-fold increases in incidence and medical treatment costs. Results: The numbers-needed-to-treat to prevent a case and cost per case averted were approximately 0.7 million and $0.6 billion for Risk Category I, 1.6 million and $1.2 billion for Risk Category II, and 9.8 million and $7.6 billion for Risk Category III. Increases of 10-fold and 100-fold in disease incidence proportionately decreased cost-effectiveness ratios. Similar levels of increases in medical treatment costs resulted in negligible changes in cost-effectiveness ratios. Conclusion: Numbers-needed-to-treat and cost-effectiveness ratios associated with preventing JE cases in U.S. travelers by vaccination varied greatly by risk category and disease incidence. While cost effectiveness ratios are not the sole rationale for decision-making regarding JE vaccination, the results presented here can aid in making such decisions under very different risk and cost scenarios. Published by Elsevier Ltd.