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Background: Yellow fever (YF) vaccines are highly effective and have a well-established safety profile despite the risk of rare serious adverse events (SAEs), vaccine-associated neurotropic (YEL-AND) and viscerotropic disease (YEL-AVD). This study aimed to describe US civilian YF vaccine usage, the population characteristics and pre-existing immunosuppressive medical conditions among those vaccinated, and to provide updated risk estimates of neurotropic and viscerotropic disease post-vaccination., Methods: A retrospective cohort study was conducted using de-identified patient information from Optum Electronic Healthcare Record (EHR) (2007-2019), Optum Clinformatics Data Mart (CDM) (2004-2019) and IBM MarketScan (2007-2019) databases. YF vaccine recipients were identified using relevant vaccination and procedural codes. Demographic characteristics and pre-existing medical conditions were described. Incidence proportions with 95% confidence intervals (CI) of neurotropic and viscerotropic diseases occurring ≤ 30 days post-vaccination, after exclusion of unlikely cases based on current clinical guidelines of YEL-AND and YEL-AVD, were calculated., Results: A total of 92,205, 46,539 and 125,235 YF vaccine recipients were retrieved from Optum EHR, Optum CDM and IBM MarketScan databases, respectively. The majority of vaccine recipients were aged < 60 years (highest proportion aged 18-29 years) with a higher proportion of females overall. Few vaccine recipients (<1%) had conditions predisposing them to immunosuppression. Four non-fatal cases of neurotropic disease and zero cases of viscerotropic disease were identified. The incidence proportion of post-vaccination neurotropic disease was 1.41 (95% CI: 0.15-6.61) and 3.04 (95% CI: 0.86-8.11) per 100,000 vaccine recipients in Optum EHR and IBM MarketScan, respectively, with no events identified in Optum CDM., Conclusions: This study provides updated insights into current YF vaccine usage in US civilian recipients and supports the safety profile of YF vaccines in US practice. The low frequency of pre-existing immunosuppressive medical conditions among vaccine recipients suggests good adherence to vaccination guidelines by healthcare practitioners. The risk of developing neurotropic and viscerotropic disease post-vaccination remains rare., (Copyright © 2021. Published by Elsevier Ltd.)