BACKGROUND: Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause acute respiratory infections (ARI) in persons of all ages. The viruses are structurally similar although HMPV lacks 2 nonstructural proteins of RSV known to suppress interferon signaling. METHODS: We analyzed data from 2 studies that prospectively enrolled hospitalized adults with ARI and compared clinical characteristics and outcomes of HMPV and RSV infection. Gene expression was compared between subjects with HMPV and RSV using DESeq2 to analyze read counts from samples of globin-reduced RNA from whole blood, sequenced using Illumina NovaSeq. RESULTS: Of 1914 illnesses evaluated, 127 (6.6%) had RSV and 90 (4.7%) had HMPV identified as a sole viral pathogen. Demographics and preexisting conditions were similar although HMPV patients had significantly less active tobacco use and numerically less underlying heart and lung disease. Sore throat, temperature >38°C, and clinically adjudicated pneumonia were significantly more frequent with HMPV compared to RSV. Restricting analysis to those subjects adjudicated as viral alone without bacterial coinfection, we identified 197 differentially expressed genes between RSV- and HMPV-infected subjects. Genes with higher expression in HMPV-infected individuals were associated with antigen binding, immunoglobulin production, and adaptive immunity. Genes increased in RSV-infected individuals were associated with NK T cells. CONCLUSIONS: Although RSV and HMPV are closely related viruses, we found differences in the clinical features of adults with HMPV patients presenting with more flu-like symptoms and viral pneumonia. Peripheral blood gene expression of hospitalized HMPV-infected patients also differed compared to those hospitalized and infected with RSV.