The live vaccine strain (LVS) of Francisella tularensis is the only vaccine against tularemia available for humans, yet its mechanism of protection remains unclear. We probed human immunological responses to LVS vaccination with transcriptome analysis using PBMC samples from volunteers at time points pre- and post-vaccination. Gene modulation was highly uniform across all time points, implying commonality of vaccine responses. Principal components analysis revealed three highly distinct principal groupings: pre-vaccination (-144 h), early (+18 and +48 h), and late post-vaccination (+192 and +336 h). The most significant changes in gene expression occurred at early post-vaccination time points (<or=48 h), specifically in the induction of pro-inflammatory and innate immunity-related genes. Evidence supporting modulation of innate effector function, specifically antigen processing and presentation by dendritic cells, was especially apparent. Our data indicate that the LVS strain of F. tularensis invokes a strong early response upon vaccination. This pattern of gene regulation may provide insightful information regarding both vaccine efficacy and immunopathogenesis that may provide insight into infection with virulent strains of F. tularensis. Additionally, we obtained valuable information that should prove useful in evaluation of vaccine lots as well as efficacy testing of new anti-F. tularensis vaccines.