This study analyzed the peripheral blood interferon stimulated gene 15(ISG15 mRNA) expression levels in viral pneumonia and bacterial pneumonia patients and discussed the possible relationship between ISG15 and the pathogenesis of viral pneumonia, providing further clinical evidences for host markers of specific respiratory virus infections. In this study, Peripheral blood samples were collected from 157 community acquired pneumonia (CAP) hospitalized patients and 40 healthy people (healthy controls) as well as their clinical data. The patients include 133 with viral respiratory tract infection and 24 patients with bacterial infection. The ISG15 mRNA expression levels for all samples were analyzed by real-time reverse transcription polymerase chain reaction(real-time RT-PCR). We validated the ISG15 mRNA expression by stimulating the peripheral blood mononuclear cell(PBMC) in vitro and analyzing the correlation between viral load and ISG15 mRNA levels. The expression level of ISG15 mRNA in the viral respiratory infection group was significantly higher than that in the healthy control group and the bacterial infection group. Receiver operating characteristic (ROC) curves analysis showed that the ISG15 mRNA in peripheral blood had a potential diagnostic value to distinguish viral respiratory infection and bacterial infection in adult CAP patients. In vitro studies also showed that there was a positive correlation between ISG15 mRNA expression in PBMC and viral replication. The peripheral blood ISG15 mRNA expression level was highly correlated with viral respiratory infection by analyzing the clinical data and in vitro experiments. This study demonstrated that ISG15 mRNA in peripheral blood may have an important clinical value in diagnosis of viral pneumonia.