BackgroundGram-positive and Gram-negative bacteria are the most common causative pathogens in community-acquired pneumonia (CAP) on the intensive care unit (ICU). The aim of this study was to determine whether the host immune response differs between Gram-positive and Gram-negative CAP upon ICU admission.Methods16 host response biomarkers providing insight into pathophysiological mechanisms implicated in sepsis and blood leukocyte transcriptomes were analysed in patients with CAP upon ICU admission in two tertiary hospitals in the Netherlands.Results309 patients with CAP with a definite or probable likelihood (determined by predefined criteria) were included. A causative pathogen was determined in 74.4% of admissions. Patients admitted with Gram-positive CAP (n=90) were not different from those admitted with Gram-negative CAP (n=75) regarding demographics, chronic comorbidities, severity of disease and mortality. Host response biomarkers reflective of systemic inflammation, coagulation activation and endothelial cell function, as well as blood leukocyte transcriptomes, were largely similar between Gram-positive and Gram-negative CAP. Blood leukocyte transcriptomes were also similar in Gram-positive and Gram-negative CAP in two independent validation cohorts. On a pathogen-specific level, Streptococcus pneumoniae and Escherichia coli induced the most distinct host immune response.ConclusionOutcome and host response are similar in critically ill patients with CAP due to Gram-positive bacteria compared with Gram-negative bacteria.