BACKGROUND: Host gene expression has emerged as a complementary strategy to pathogen detection tests for the discrimination of bacterial and viral infection. The impact of immunocompromise on host-response tests remains unknown. We evaluated a host-response test discriminating bacterial, viral, and noninfectious conditions in immunocompromised subjects. METHODS: An 81-gene signature was measured using real-time-polymerase chain reaction in subjects with immunocompromise (chemotherapy, solid-organ transplant, immunomodulatory agents, AIDS) with bacterial infection, viral infection, or noninfectious illness. A regularized logistic regression model trained in immunocompetent subjects was used to estimate the likelihood of each class in immunocompromised subjects. RESULTS: Accuracy in the 136-subject immunocompetent training cohort was 84.6% for bacterial versus nonbacterial discrimination and 80.8% for viral versus nonviral discrimination. Model validation in 134 immunocompromised subjects showed overall accuracy of 73.9% for bacterial infection (P = .04 relative to immunocompetent subjects) and 75.4% for viral infection (P = .30). A scheme reporting results by quartile improved test utility. The highest probability quartile ruled-in bacterial and viral infection with 91.4% and 84.0% specificity, respectively. The lowest probability quartile ruled-out infection with 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. Performance was independent of the type or number of immunocompromising conditions. CONCLUSIONS: A host gene expression test discriminated bacterial, viral, and noninfectious etiologies at a lower overall accuracy in immunocompromised patients compared with immunocompetent patients, although this difference was only significant for bacterial infection classification. With modified interpretive criteria, a host-response strategy may offer clinically useful diagnostic information for patients with immunocompromise.